BRPI0808301B1 - Compound and pharmaceutical composition - Google Patents

Abstract

COMPOUND, PHARMACEUTICAL COMPOSITION, METHOD FOR TREATMENT OF PROLIFERATIVE CELL DISORDER, METHOD FOR TREATMENT OR PROPHYLAXIS OF CANCER AND METHOD FOR TREATMENT OR PROPHYLAXIS OF A NEURODEGENERATIVE DISEASE. The present invention relates to HSP90 inhibitors containing the fused amino pyridine core that are useful as inhibitors of HSP90 and their use in the treatment of HSP90 related diseases and disorders such as cancer, an autoimmune disease, or a neurodegenerative disease.

Description

field of invention

[0001] HSP90s are ubiquitous chaperone proteins that are involved in the folding and self-protein stabilization of a wide range of proteins, including key proteins involved in signal translation, cell cycle control, and transcriptional regulation. The researchers who reported that the HSP90 chaperone proteins are associated with important signaling proteins such as steroid hormone receptors and protein kinases, including, for example, the Raf-1 kinase family, EGFR, v-Src, Cdk4, and ErbB- 2, many of which are overexpressed or mutated in various cancers (Bucher J. TIBS, 1999, 24, 136-141; Stepanova, L., et al., "Genes Dev.", 1996, 10, 1491-502 ; Hence, K., et al., "J. Biol. Chem.", 1996, 271, 22030-4). Additional studies indicate that certain co-chaperones, eg, HSP70, p60/Hop/Stil, Hip, Bag1, HSP40/Hdj2/Hsjl, immunophilins, p23, and p50, may assist HSP90 in its functions (Caplan, “A. Trends in Cell Biol.", 1999, 9, 262-68).

[0002] HSP90 has been shown by mutational analysis to be necessary for the survival of normal eukaryotic cells. However, HSP90 is overexpressed in many tumor types indicating that it may play a significant role in cancer cell survival and that cancer cells may be more sensitive to HSP90 inhibition than normal cells. For example, cancer cells typically have large numbers of mutations and overexpressed oncoproteins that are dependent on HSP90 for folding. In addition, because the environment of a tumor is typically hostile due to hypoxia, nutrient deprivation, acidosis, etc., tumor cells may be especially dependent on HSP90 for survival. Furthermore, inhibition of HSP90 causes simultaneous inhibition of a large number of client oncoproteins as well as hormone receptors and transcription factors making it an attractive target for an anti-cancer agent. Indeed, the benzoquinone ansamycins, a family of natural products that inhibit HSP90, have demonstrated clear therapeutic activity on clinical examination. Many promising ansamycins related to HSP90 inhibitors are currently designated in clinical examination, 17-allylamino,17-demethoxygeldanamycin (17-AAG), 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) and IPI-504. Another class of HSP90 inhibitors is a small synthetic purine support molecule ("scaffold"). Currently, many of the purine-supporting HSP90 inhibitors have demonstrated positive preclinical results; with the candidate with the best odds being CNF-2024, which is currently in phase 1 clinical examination.

[0003] Recent studies suggest that heat shock proteins (HSPs) play an important role in neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington (HD) (luo, G-r. "Int. J. Biol. Sci.", 2007, 3(1), 20-26; Dickey, C., "J. Clin. Invest.", 2007, 117(3) ), pp. 648-658). Manipulation of HSPs, such as downregulation of HSP90 or upregulation of HSP70, has been shown to provide beneficial effects in many neurodegenerative disorders both by reducing protein aggregation and by facilitating the folding property of proteins to restore their function.

[0004] Drugs targeting the HSP90 protein are entirely new in cancer and therapies for neurodegenerative diseases. Research related to HSP90 is rapidly developing and hence the need for new and existing active compounds. As such, this invention relates to fused aminopyridine compounds useful as inhibitors of HSP90.

Summary of the invention

[0005] The present invention relates to HSP90 inhibitors containing the fused aminopyridine core that are useful as HSP90 inhibitors and their use in the treatment of HSP90 related diseases and disorders such as cancer, an autoimmune disease, or a neurodegenerative disease. .

ou seus isômeros geométricos, enantiômeros, diasterômeros, racematos, sais farmaceuticamente aceitáveis, pró-farmacos e solvatos dos mesmos, onde: U é N ou CH; W é hidrogênio, halogênio, amino, hidróxi, tiol, alquila, alquila substituído, alcoxi substituído ou não substituído, alquilamino substituído ou não substituído, dialquilamino substituído ou não substituído, alquiltio substituído ou não substituído, alquilsulfonila substituído ou não substituído, CF3, NO2, CN, N3, sulfonila, acila, arila, arila substituído, heteroarila, heteroarila substituído, heterocíclico, heterocíclico substituído, cicloalquila, ou cicloalquila substituído; X é ausente, O, S, S(O), S(O)2, N(R8), C(O), CF2, C(R8) ou alquila C2-C6, alquenila C2-C6, alquinila C2-C6, no qual um ou mais metilenos podem ser interrompidos ou terminados por O, S, SO, SO2, N(R8), C(O), onde R8 é hidrogênio, acila, alifático ou alifático substituído; Y é independentemente hidrogênio, halogênio, NO2, CN, ou alquila inferior; Z é amina, alquilamino substituído ou não substituído, dialquilamino substituído ou não substituído, alquilcarbonilamino substituído ou não substituído; Q é arila, arila substituído, heteroarila, heteroarila substituído, cicloalquila, ou heterocicloalquila; V é hidrogênio, linear ou ramificado, alquila substituído ou não substituído, alquenila substituído ou não substituído, alquinila substituído ou não substituído, o qual um ou mais metilenos podem ser interrompidos ou terminados por O, S, S(O), SO2, N(R8), C(O), arila substituído ou não substituído, heteroarila substituído ou não substituído, heterocíclico substituído ou não substituído; cicloalquila substituído ou não substituído; onde R8 é hidrogênio, acila, alifática ou alifática substituído.[0006] Accordingly, the present invention provides a compound having the general formula:

or geometric isomers, enantiomers, diasteromers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, where: U is N or CH; W is hydrogen, halogen, amino, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2 , CN, N3 , sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; X is absent, O, S, S(O), S(O)2, N(R8), C(O), CF2, C(R8) or C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl , in which one or more methylenes may be interrupted or terminated by O, S, SO, SO2, N(R8), C(O), where R8 is hydrogen, acyl, aliphatic or substituted aliphatic; Y is independently hydrogen, halogen, NO 2 , CN, or lower alkyl; Z is amine, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; Q is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or heterocycloalkyl; V is hydrogen, linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, which one or more methylenes may be interrupted or terminated by O, S, S(O), SO2, N (R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl; substituted or unsubstituted cycloalkyl; where R8 is hydrogen, acyl, aliphatic or substituted aliphatic.

Detailed description of the invention

[0007] In a first configuration of the compounds of the present invention are the compounds represented by formula (I) as illustrated above, or their geometric isomers, enantiomers, diasteromers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof.

onde X2 e X5 são independentemente CR21 ou N; R21-R23 são independentemente selecionados a partir do grupo consistindo de hidrogênio, halogênio, amina, amino substituído, hidroxi, hidroxi substituído, tiol, tiol substituído, alquila, alquila substituído, alquenila, alquenila substituído, alquinila, alquinila substituído, alcoxi substituído ou não substituído, alquilamino substituído ou não substituído, dialquilamino substituído ou não substituído, alquiltio substituído ou não substituído, alquilsulfonila substituído ou não substituído, CF3, NO2, CN, N3, carbonila substituído, sulfonila, acila, arila, arila substituído, heteroarila, heteroarila substituído, heterocíclico, heterocíclico substituído, cicloalquila, ou cicloalquila substituído; R22 e R23 podem ser tomados juntos a partir do carbono ao qual eles estão ligados para formar um anel cíclico saturado ou insaturado fundido de 5-8 membros, opcionalmente, substituído com 0-3 heteroátomo; M1 está ausente, alquila C1-C6, alquenila C2-C6, alquinila C2C6, arila ou heteroarila; M2 está ausente, O, S, SO, SO2, N(R8), ou C=O; M3 está ausente, C=O, O, S, SO, SO2 ou N(R8); M4 é hidrogênio, halogênio, CN, N3, Hidroxi, hidroxi substituído, amina, amino substituído, CF3, alquila C1-C6, alquenila C2-C6, alquinila C2-C6, cicloalquila, heterocíclico, arila ou heteroarila; e X, Y e Z, são como previamente definidos.[0008] In a second configuration of the compounds of the present invention are the compounds represented by formula (II) as illustrated below, or their geometric isomers, enantiomers, diasteromers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof.

where X2 and X5 are independently CR21 or N; R21-R23 are independently selected from the group consisting of hydrogen, halogen, amine, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy substituted, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , heterocyclyl, substituted heterocyclyl, cycloalkyl, or substituted cycloalkyl; R22 and R23 can be taken together from the carbon to which they are attached to form a 5-8 membered saturated or unsaturated fused cyclic ring, optionally substituted with 0-3 heteroatom; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, Hydroxy, substituted hydroxy, amine, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and X, Y and Z, are as previously defined.

[0009] In one example, X2 and X5 are independently CH or N, R21-R23 are independently selected from the group consisting of hydrogen, halogen, amine, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, alkylamino substituted or unsubstituted, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl or substituted cycloalkyl; R22 and R23 can be taken together from the carbon to which they are attached to form a saturated or unsaturated fused 5-8 membered cyclic ring, optionally substituted with 0-3 heteroatoms; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, Hydroxy, amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and X, Y and Z are as previously defined.

onde X1-X5 são independentemente N ou CR21, onde R21 é independentemente selecionado a partir do grupo consistindo de hidrogênio, halogênio, amina, amino substituído, hidroxi, hidroxi substituído, tiol, tiol substituído, alquila, alquila substituído, alquenila, alquenila substituído, alquinila, alquinila substituído, alcoxi substituído ou não substituído, alquilamino substituído ou não substituído, dialquilamino substituído ou não substituído, alquiltio substituído ou não substituído, alquilsulfonila substituído ou não substituído, CF3, NO2, CN, N3, carbonila substituído, sulfonila, acila, arila, arila substituído, heteroarila, heteroarila substituído, heterocíclico, heterocíclico substituído, cicloalquila, ou cicloalquila substituído; M1 está ausente, alquila C1-C6, alquenila C2-C6, alquinila C2-C6, arila ou heteroarila; M2 está ausente, O, S, SO, SO2, N(R8), ou C=O; M3 está ausente, C=O, O, S, SO, SO2 ou N(R8); M4 é hidrogênio, halogênio, CN, N3, Hidroxi, hidroxi substituído, amina, amino substituído, CF3, alquila C1-C6, alquenila C2-C6, alquinila C2C6, cicloalquila, heterocíclico, arila ou heteroarila; e X, Y e Z são como previamente definidos. Em um exemplo, X é S; Y é hidrogênio; Z é amina; M1-M4 e X1-X5 são como definidos acima.[0010] In a third configuration, the compounds of the present invention are compounds represented by formula (III) as illustrated below, or their geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

where X1-X5 are independently N or CR21, where R21 is independently selected from the group consisting of hydrogen, halogen, amine, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, Hydroxy, substituted hydroxy, amine, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and X, Y and Z are as previously defined. In one example, X is S; Y is hydrogen; Z is amine; M1-M4 and X1-X5 are as defined above.

[0011] In one example, X1-X5 are, independently, N or CR21, where R21 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, substituted alkylamino or unsubstituted, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl , or substituted cycloalkyl; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, Hydroxy, amine, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and X, Y and Z are as previously defined. In one example, X is S; Y is hydrogen; Z is amine; M1-M4 and X1-X5 are as defined above.

onde X2 e X5 são independentemente CH ou N; R21 é independentemente selecionado a partir do grupo consistindo de hidrogênio, halogênio, amina, amino substituído, hidroxi, hidroxi substituído, tiol, tiol substituído, alquila, alquila substituído, alquenila, alquenila substituído, alquinila, alquinila substituído, alcoxi substituído ou não substituído, alquilamino substituído ou não substituído, dialquilamino substituído ou não substituído, alquiltio substituído ou não substituído, alquilsulfonil substituído ou não substituído, CF3, NO2, CN, N3, carbonila substituído, sulfonila, acila, arila, arila substituído, heteroarila, heteroarila substituído, heterocíclico, heterocíclico substituído, cicloalquila, ou cicloalquila substituído; Cy é um anel cíclico saturado ou insaturado fundido de 5-8 membros, opcionalmente, substituído com 0-3 heteroátomos; M1 está ausente, alquila C1-C6, alquenila C2-C6, alquinila C2-C6, arila ou heteroarila; M2 está ausente, O, S, SO, SO2, N(R8), ou C=O; M3 está ausente, C=O, O, S, SO, SO2 ou N(R8); M4 é hidrogênio, halogênio, CN, N3, Hidroxi, hidroxi substituído, amina, amino substituído, CF3, alquila C1-C6, alquenila C2-C6, alquinila C2C6, cicloalquila, heterocíclico, arila ou heteroarila; e X, Y e Z são como previamente definidos acima. Em um exemplo, X é S; Y é hidrogênio; Z é amina; R21, M1-M4 e X2, X5 são como definidos acima.[0012] In a fourth configuration, the compounds of the present invention are compounds represented by formula (IV) as illustrated below, or their geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

where X2 and X5 are independently CH or N; R21 is independently selected from the group consisting of hydrogen, halogen, amine, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic , substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Cy is a 5-8 membered saturated or unsaturated fused cyclic ring, optionally substituted with 0-3 heteroatoms; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, Hydroxy, substituted hydroxy, amine, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and X, Y and Z are as previously defined above. In one example, X is S; Y is hydrogen; Z is amine; R21, M1-M4 and X2, X5 are as defined above.

[0013] In one example, X2 and X5 are independently CH or N; R21 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, alkylsulfonyl substituted or unsubstituted, CF3, NO2, CN, N3, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Cy is a 5-8 membered saturated or unsaturated fused cyclic ring, optionally substituted with 0-3 heteroatoms; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, hydroxy, amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and X, Y and Z are as previously defined above. In one example, X is S; Y is hydrogen; Z is amine; R21, M1-M4 and X2, X5 are as defined above.

onde X2 e X5 são independentemente CH ou N; R21 é independentemente selecionado a partir do grupo consistindo de hidrogênio, halogênio, amina, amino substituído, hidroxi, hidroxi substituído, tiol, tiol substituído, alquila, alquila substituído, alquenila, alquenila substituído, alquinila, alquinila substituído, alcoxi substituído ou não substituído, alquilamino substituído ou não substituído, dialquilamino substituído ou não substituído, alquiltio substituído ou não substituído, alquilsulfonil substituído ou não substituído, CF3, NO2, CN, N3, carbonila substituído, sulfonila, acila, arila, arila substituído, heteroarila, heteroarila substituído, heterocíclico, heterocíclico substituído, cicloalquila, ou cicloalquila substituído; Y1 e Y3 são independentemente O, S N(R8), CH(R21); n é 1, 2, ou 3; M1 está ausente, alquila C1-C6, alquenila C2-C6, alquinila C2-C6, arila ou heteroarila; M2 está ausente, O, S, SO, SO2, N(R8), ou C=O; M3 está ausente, C=O, O, S, SO, SO2 ou N(R8); M4 é hidrogênio, halogênio, CN, N3, hidroxi, hidroxi substituído, amina, amino substituído, CF3, alquila C1-C6, alquenila C2-C6, alquinila C2C6, cicloalquila, heterocíclico, arila ou heteroarila; R10 e R20 são independentemente hidrogênio, alquila, alquila substituído, arila ou arila substituído; e X, Y e Z são como previamente definidos. Em um exemplo, X é S; Y é hidrogênio; Z é amino; n, R21, M1-M4 e X2, X5 , Y1 e Y3 são como definidos acima.[0014] In a fifth configuration, the compounds of the present invention are the compounds represented by formula (V) as illustrated below, or their geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

where X2 and X5 are independently CH or N; R21 is independently selected from the group consisting of hydrogen, halogen, amine, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic , substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Y1 and Y3 are independently O, SN(R8), CH(R21); n is 1, 2, or 3; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, hydroxy, substituted hydroxy, amine, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R10 and R20 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; and X, Y and Z are as previously defined. In one example, X is S; Y is hydrogen; Z is amino; n, R21, M1-M4 and X2, X5, Y1 and Y3 are as defined above.

[0015] In one example, X2 and X5 are independently CH or N; R21 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, alkylsulfonyl substituted or unsubstituted, CF3, NO2, CN, N3, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Y1 and Y3 are independently O, S, N(R8), CH(R21); n is 1, 2, or 3; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, hydroxy, substituted hydroxy, amine, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R10 and R20 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; and X, Y and Z are as previously defined. In one example, X is S; Y is hydrogen; Z is amino; n, R21, M1-M4 and X2, X5, Y1 and Y3 are as defined above.

[0016] Representative compounds according to the invention are those selected from Table A below or their geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof.

[0017] The invention further provides methods for the prevention or treatment of diseases or conditions involving abnormal proliferations, differentiation or survival of cells. In one embodiment, the invention further provides the use of one or more compounds of the invention in the manufacture of a medicament for arresting or decreasing diseases involving abnormal proliferation, differentiation, or survival of cells. In a preferred embodiment, the disease is cancer or neurodegenerative disease. In one embodiment, the invention pertains to a method of treating cancer in a subject in need of treatment, comprising administering to said subject a therapeutically effective amount of a compound of the invention. In one embodiment, the invention pertains to a method for treating a neurodegenerative disease in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of the compound of the invention.

[0018] The term “cancer” refers to any cancer caused by the proliferation of malignant neoplastic cells such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, mesotheliomas, leukemias, and lymphomas such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphomas, human T-cell lymphotropic virus (HTLV)-associated lymphomas. such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Additional examples include myelodysplasia syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms tumor, bone tumors, and soft tissue sarcoma, solid tumors common in adults such as head and neck cancers (e.g., oral , laryngeal, nasopharyngeal, and esophageal), genitourinary cancers (eg, prostate, bladder, kidney, uterine, ovarian, testicular), lung cancer (eg, small cell and non-small cell), breast cancer, pancreatic cancer , melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin syndrome (eg, medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancers that can be treated by the object compounds of the present invention include, but are not limited to, skeletal and smooth muscle cancer, stomach cancer, small intestine cancer, rectal carcinoma, salivary gland cancer, cancer endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0019] Additional cancers that the compounds described herein may be useful in preventing, treating and studying are, for example, colon carcinoma, familial adenomatous polyposis carcinoma (adenomatous polyps), and hereditary non-polyposis colorectal cancer, or melanoma. Additionally, cancers include, but are not limited to, labial carcinoma, laryngeal carcinomas, hypopharyngeal carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), renal carcinoma , renal parenchyma carcinoma, cervical carcinoma, uterine body carcinoma, endometrial carcinoma, chorion carcinoma, testicular carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gallbladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, tetratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect of the invention, the present invention provides for the use of one or more compounds of the invention in the manufacture of a medicament for the treatment of cancer.

[0020] In one embodiment, the present invention includes the use of one or more compounds of the invention in the manufacture of a medicament that further prevents abnormal proliferation, differentiation, or survival of cells. For example, compounds of the invention may be useful in preventing tumors from increasing in size or from reaching a metastatic state. The subject compounds of the invention can be administered to stop the progression or advancement of cancer. In addition, the example of the invention includes the use of the object compound of the invention to prevent a recurrence of cancer.

[0021] This invention further encompasses the treatment or prevention of cell proliferative disorders such as hyperplasia, dysplasia and pre-cancer lesions. Dysplasia is the early form of pre-cancer lesion recognized on a biopsy by a pathologist. The object compounds of the present invention can be administered for the purpose of preventing said hyperplasia, dysplasias or pre-cancer lesions from the expansion continuity or from the cancer itself. Examples of pre-cancer lesions can occur in the skin, esophageal tissue, breast and cervical intraepithelial tissue.

[0022] "Combination therapy" includes the administration of the subject compounds in additional combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to a, surgery or radiation treatment). For example, compounds of the invention can be used in combination with other pharmaceutically active compounds, preferably compounds that are capable of enhancing the effect of the compounds of the invention. Compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially with the other drug therapy. In general, a combination therapy provides for the administration of two or more drugs during a single cycle or course of therapy.

[0023] In one aspect of the invention, the subject compounds may be administered in combination with one or more separate agents that modulate protein kinases involved in various disease states. Examples of such kinases may include, but are not limited to: specific serine/threonine kinases, receptor-specific tyrosine kinases, and non-receptor-specific tyrosine kinases. Serine/threonine kinases include mitogen-activated protein kinases (MAPK), meiosis-specific kinase (MEK), RAF and aurora kinase. Examples of receptor kinase families include epidermal growth factor receptor (EGFR) (e.g. HER2/neu, HER3, HER4, ErbB, ErbB2, ErbB3, ErbB4, Xmrk, DER, Let23); fibroblast growth factor (FGF) receptor (e.g., FGF-R1, GFF-R2/BEK/CEK3, FGF-R3/CEK2, FGF-R4/TKF, KGF-R); hepatocyte growth/dispersion factor receptor (HGFR) (eg, MET, RON, SEA, SEX); insulin receptor (eg, IGFI-R); Eph (e.g. CEK5, CEK8, EBK, ECK, EEK, EHK-1, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDK5, SEK); Axl (eg, Mer/Nyk, Rse); RET, and platelet-derived growth factor receptor (PDGFR) (e.g., PDGFα-R, PDGFβ-R, CSF1-R/FMS, SCF-R/C-K1T, VEGF-R/FLT, NEK/FLK, FLT3/FLK2/STK-1). Non-receptor tyrosine kinase families include, but are not limited to, BCR-ABL (eg, p43abl, ARG); BTK (e.g. ITK/EMT, TEC); CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK and SYk.

[0024] In another aspect of the invention, the subject compounds may be administered in combination with one or more agents that modulate non-kinase biological targets or processes. Such targets include histone deacetylases (HDAC), DNA methyltransferase (DNMT), heat shock proteins (eg, HSP90), and proteasomes.

[0025] In a preferred embodiment, the subject compounds may be combined with antineoplastic agents (e.g., small molecules, monoclonal antibodies, antisense RNA, and fusion proteins) that inhibit one or more biological targets such as Zolinza, Tarceva , Iressa, Tykerb, Gleevec, Sutent, Sprycel, Nexavar, Sorafinib, CNF2024, RG108, MBS387032, Affinitak, Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD184322, Obatodax, ABT737 and AEE788. Such combinations may enhance therapeutic efficacy over the efficacy achieved by either agent alone and may prevent or delay the emergence of resistant mutational variants.

[0026] In certain preferred embodiments, compounds of the invention are administered in combination with a chemotherapeutic agent. Chemotherapeutic agents encompass a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purpose of shrinking tumors, destroying remaining cancer cells left after surgery, inducing remission, maintaining remission, and/or alleviating symptoms related to the cancer or its treatment. Examples of such agents include, but are not limited to, alkylating agents such as mustard gas derivatives (Mechlorethanim, cylophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimines (thiotepa, hexamethylmelamine), alkyl sulfonates (Busulfan), hydrazines and triazines ( Altretamine, Procarbazine, Dacarbazine and Temozolomide), Nitroureas (Carmustine, Lomustine and Streptozocin), Ifosfamide and metal salts (Carboplatin, Cisplatin, and Oxaliplatin), plant alkaloids such as Podophyllotoxins (Etoposide and Tenisopide), Taxanes (Paclitaxel and Docetaxel), Vinca alkaloids (Vincristine, Vinblastine, Vindesine and Vinorelbine), and Camptotecan analogues (Irinotecan and Topotecan); anti-tumor antibodies such as Chromomycins (Dactinomycin and Plicamycin), Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, Vlarubicin and Idarubicin), and miscellaneous antibodies such as Mitomycin, Actinomycin and Bleomycin; antimetabolites such as folic acid antagonists (Methotrexate, Pemetrexed, Taltitrexed, Aminopterin), pyrimidine antagonists (5-Fluorouracil, Floxuridine, Cytarabine, Capcitabine, and Gemcitabine), purine antagonists (6-Mercaptopurine and 6-thioguanine) and adenosine deaminase (Cladribine, Fludarabine, Mercaptopurine, Clofarabine, Thioguanine, Nelarabine and Pentostatin); topoisomerase inhibitors such as topoisomerase I inhibitors (Ironotecan, topotecan) and topoisomerase II inhibitors (Amsacrine, etoposide, etoposide phosphate, teniposide); monoclonal antibodies (Alemtuzumab, Gemtuzumab ozogamicin, Rituximab, Trastuzumab, Ibritumomab Tioxetan, Cetuximab, Panimumab, Tositumomab, Bevacizumab), and miscellaneous antineoplastics such as ribonucleotide reductase inhibitors (Hydroxyurea); adrenocortical steroid inhibitor (Mitotane); enzymes (Asparaginase and Pegaspargase); antimicrobial agents (Estramustine); and retinoids (Bexarotene, Isotretinoin, Tretinoin (ATRA).

[0027] In certain preferred embodiments, compounds of the invention are administered in combination with a chemoprotective agent. Chemoprotective agents work to protect the body or minimize the side effects of chemotherapy. Examples of such agents include, but are not limited to, amfostine, mesna, and dexrazoxane.

[0028] In one aspect of the invention, the subject compounds are administered in combination with radiation therapy. Radiation is commonly released internally (implantation of radioactive material near the cancer site) or externally from a machine employing photon (x-ray or gamma ray) or particle radiation. Where the combination therapy further comprises radiation treatment, the radiation treatment may be conducted at any suitable time provided that a beneficial effect is achieved from the joint action of the combination of the therapeutic agents and radiation treatment. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporarily removed from the administration of the therapeutic agents, perhaps for days or even weeks.

[0029] It will be appreciated that compounds of the invention may be useful in the treatment of disorders such as, but not limited to: anti-proliferative disorders (e.g., cancers); neurodegenerative diseases including Huntington's Disease, Polyglutamine Disease, Parkinson's Disease, Alzheimer's Disease, Seizures/epilepsy, striatonigral degeneration, Progressive supranuclear palsy, Torsion dystonia, spasmodic torticollis and dyskinesia, Familial tremor, Gilles de La Tourette's syndrome, Lewy body syndrome, Progressive supranuclear palsy, Pick's disease, Intracerebral hemorrhage, Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia, Shy's syndrome progressive ataxia -Drager; Metabolic diseases including type 2 diabetes; Degenerative eye diseases including Glaucoma, age-related muscle degeneration, glaucoma rubeotic; inflammatory diseases and/or immune system disorders including Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile Chronic Arthritis, Graft versus Host Disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, Inflammatory Bowel Diseases, Ulcerative Colitis, Alcoholic Hepatitis, Diabetes, Sjoegren's syndrome, Multiple sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain, Systemic lupus erythematosus; Disease involving angiogenesis including cancer, psoriasis, rheumatoid arthritis; psychological disorders including bipolar disorder, schizophrenia, mania, depression and dementia; Cardiovascular diseases including heart failure, restenosis and arteriosclerosis; Fibrotic diseases including liver fibrosis, cystic fibrosis and angiofibroma; Infectious diseases including fungal infections such as candidiasis or Candida albicans, Bacterial infections, Viral infections such as Herpes Simplex, poliovirus, rhinovirus and Coxsacke virus (intestinal), Protozoal infections such as Malaria, Leishmania infection, Trypanosome brucei infection, Toxoplasmosis and coccidiosis and hematopoietic disorders including thalassemia, anemia and sickle cell anemia.

[0030] In one embodiment, compounds of the invention can be used to induce or inhibit apoptosis, a physiological process of cell death critical for normal development and homeostasis. Changes in apoptotic pathways contribute to the pathogenesis of a variety of human diseases. Compounds of the invention, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with alterations in apoptosis including cancer (particularly, but not limited to, follicular lymphomas with p53 mutations, breast, prostate and ovarian dependent tumors). hormones, and precancerous lesions such as familial adenomatous polyposis), viral infections (including, but not limited to, herpes virus, smallpox or syphilis, Epstein-Barr virus, Sindbis virus, and adenovirus), autoimmune diseases (including , but not limited to, systemic lupus erythematosus, immune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration), AIDS, myelodysplastic syndromes as, aplastic anemia, myocardial infarctions associated with ischemic injury, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-induced liver disease, hematologic disorders (including, but not limited to, chronic anemia and aplastic anemia) , degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.

[0031] In addition to anti-cancer and anti-tumor activity, HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammatory agents, anti-infectious disease agents, agents for treating immunity, agents for treating shock, ischemia, multiple sclerosis, cardiac disorder, disorders related to the central nervous system, and agents useful in promoting nerve regeneration (See, for example, Rosen et al, WO 02/09696 (PCT/US01/ 23640); Degranco et al., WO 99/51223 (PCT/US99/07242); Gold, US Patent No. US 6,210,974 B1 ; DeFranco et al, US Patent No: US 6,174,875 ). These are reports in the literature that fibrogenetic disorders including, but not limited to, scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis of the liver, keloid formation, interstitial nephritis, and pulmonary fibrosis can also be treated with HSP90 inhibitors.

[0032] In one aspect the invention provides the use of compounds of the invention for the treatment and/or prevention of immune response or immune mediated responses and diseases, such as the prevention or treatment of rejection following transplantation of material, organs or tissue from synthetic or organic graft, to replace all or part of tissue functions, such as heart, kidney, liver, bone marrow, skin, cornea, vessels, lung, pancreas, intestine, limb, muscle, nervous tissue, duodenum, small intestine, pancreatic islet cells, including xenografts, etc.; to treat or prevent graft versus host disease, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, thyroiditis, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, juvenile or recent onset diabetes mellitus, uveitis , Graves' disease, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, vasculitis, autoantibody-mediated diseases, aplastic anemia, Evan's syndrome, autoimmune hemolytic anemia, and the like; and additionally to treat infectious diseases causing abnormal immune response and/or activation, such as traumatic or pathogen-induced immune dysregulation, including, for example, those caused by hepatitis B and C infections, Staphylococcus aureus infection, encephalitis viral, sepsis, parasitic diseases where damage is induced by an inflammatory response (eg, leprosis); and to prevent or treat circulatory diseases, such as arteriosclerosis, atherosclerosis, vasculitis, polyarthritis nodosa, and myocarditis. In addition, the present invention can be used to prevent/suppress an immune response associated with a gene therapy treatment, such as the introduction of foreign genes into autologous cells and the expression of the encoded product. Thus in one embodiment, the invention relates to a method of treating a disease or immune response disorder or a mediated immune response or disorder in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of a compound of the invention.

[0033] In one aspect, the invention provides the use of compounds of the invention in the treatment of a variety of neurodegenerative diseases, a non-exhaustive list of which includes: I. Disorders characterized by progressive dementia in the absence of other prominent neurological signs, such as Alzheimer's disease; senile dementia of the Alzheimer's type; and Pick's disease (lobar atrophy); II. Syndromes combining progressive dementia with other prominent neurologic abnormalities, such as: A) syndromes appearing primarily in adults (eg, Huntington's disease, multiple systemic atrophy combining dementia with ataxia and/or manifestations of Parkinson's disease, progressive supranuclear palsy (Steel- Richardson-Olszewski), diffuse Lewy body disease, and corticodentatonigral degeneration); and B) syndromes appearing primarily in children or young adults (eg, Hallervorden-Spatz disease and progressive familial myoclonic epilepsy); III. Gradually developing syndromes of posture and movement abnormalities such as agitating palsy (Parkinson's disease), striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsional spasm; deforming muscular dystonia), spasmodic torticollis and other dyskinesias, familial tremor, and Gilles de La Tourette syndrome; IV. Progressive ataxia syndromes such as cerebellar degenerations (e.g., cerebellar cortical degeneration and olivopontocerebellar atrophy (OPCA)); and spinocerebellar degeneration (Friedreich's ataxia and related disorders); V. Central autonomic nervous system failure syndrome (Shy-Drager syndrome); SAW. Syndromes of muscle weakness and wasting without sensory changes (motor neuron disease such as amyotrophic lateral sclerosis, spinal muscular atrophy (e.g. infantile spinal muscular atrophy (Werdnig-Hoffman), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander) and other forms of spinal muscular atrophy), primary lateral sclerosis, and hereditary spastic paraplegia VII. Syndromes combining muscle weakness and wasting with sensory changes (progressive neural muscular atrophy; chronic familial polyneuropathies) such as peroneal muscular atrophy (Charcot-Marie-Tooth) , hypertrophic interstitial polyneuropathy (Dejerine-Sottas), and miscellaneous forms of chronic progressive neuropathy VIII.Progressive visual loss syndromes such as retinal pigmentation degeneration (retinitis pigmentosa), and hereditary optic atrophy (Leber's disease). compounds of the invention may be involved in chromatin remodeling.

[0034] The invention encompasses pharmaceutical compositions comprising pharmaceutically acceptable salts of the compounds of the invention as described above. The invention also encompasses pharmaceutical compositions comprising hydrates of the compounds of the invention. The term "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate and the like. The invention further comprises pharmaceutical compositions comprising any solid or liquid physical form of the compound of the invention. For example, compounds can be in crystalline form, in amorphous form, and have any particle size. The particles may be micronized, or they may be agglomerated, particulate granules, powders, oils, oily suspensions, or any other form, liquid or solid physical form.

[0035] The compounds of the invention, and derivatives, fragments, analogs, homologs, pharmaceutically acceptable salts or hydrates thereof can be incorporated into pharmaceutical compositions suitable for administration, together with a pharmaceutically acceptable carrier or excipient. Such compositions typically comprise a therapeutically effective amount of any of the above compounds, and a pharmaceutically acceptable carrier. Preferably, the amount effective when treating a cancer is an amount effective to selectively induce terminal differentiation of suitable neoplastic cells and less than an amount that would cause toxicity in a patient.

[0036] It will be appreciated that the compounds of the present invention may be used in combination with an immunotherapeutic agent. One form of immunotherapy is the generation of an active systemic tumor-specific immune response from the host of origin by administering a vaccine composition to a site distant from the tumor. Several types of vaccines have been proposed, including isolated tumor-antigen vaccines and anti-idiotype vaccines. Another search is for use of tumor cells from the subject to be treated, or a derivative of said cells (reviewed by Schirrmacher et al., (1995), "J. Cancer Res. Clin. Oncol.", 121:487) . In U.S. Patent No.: 5,484,596, Hanna Jr. Et a., claims a method for treating an amputable/operable carcinoma to prevent recurrence or metastases, comprising surgically removing the tumor, dispersing the cells with collagenase, irradiating the cells, and vaccinating the patient with at least three consecutive doses of about 107 cells.

[0037] It will be appreciated that the compounds of the invention may be advantageously used in conjunction with one or more other therapeutic agents. Examples of suitable agents for secondary therapy include a 5HT1 agonist, such as a triptan (e.g. sumatriptan or naratriptan); an adenosine A1 agonist; an EP linker; an NMDA modulator, such as a glycine antagonist; a sodium channel blocker (eg, lamotrigine); a substance P antagonist (e.g., an NK1 antagonist); a cannabinoid; acetaminophen or phenacetin; a lipoxygenase-5 inhibitor; a leukotriene receptor antagonist; a DMARD (eg, methotrexate); gabapentin and related compounds; a tricyclic antidepressant (eg, amitriptyline); a neuron-stabilizing antiepileptic drug; a mono-aminergic uptake inhibitor (eg, venlafaxine); a matrix metalloproteinase inhibitor; a nitric oxide synthesis (NOS) inhibitor, such as an iNOS or an inhibitor of nNOS; an inhibitor of the release, or action, of tumor necrosis factor-alpha; an antibody therapy, such as a monoclonal antibody therapy; an antiviral agent, such as a nucleoside inhibitor (e.g., lamivudine) or an immune system modulator (e.g., interferon); an opioid analgesic; a local anesthetic; a stimulant, including caffeine; an H2 antagonist (e.g. ranitidine); a proton pump inhibitor (eg, omeprazole); an antacid (e.g. aluminum or magnesium hydroxide; an anti-flatulence (e.g. simethicone); a decongestant (e.g. phenylephrine, phenylpropanolamine; pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylemetazoline, propylhexedrine, or levo-desoxyephedrine ); an antitussive (eg, codeine, hydrocodone, carmifen, carbetapentane, or dextramethorphan); a diuretic; or a sedating or non-sedating antihistamine.

[0038] The compounds of the invention may be administered by any suitable means, including, without limitation, parenteral, intravenous, intramuscular, subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, vaginal, rectal, and transmucosal or similar. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Pharmaceutical preparations include a solid, semi-solid or liquid preparation (tablet, pellet, lozenge, capsule, suppository, cream, ointment, aerosol, powder, liquid, emulsion, suspension, syrup, injection, etc.) containing a compound of the invention as a active ingredient, which is suitable for the selected mode of administration. In one embodiment, the pharmaceutical compositions are administered orally, and are therefore formulated in a form suitable for oral administration, i.e., as a solid or a liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescents, powders, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment of the present invention, the composition is formulated into a capsule. According to this embodiment, the compositions of the present invention comprise, in addition to the active compound and the inert carrier or diluent, a hard gelatine capsule.

[0039] Any inert excipient that is commonly used as a carrier or diluent can be used in the formulations of the present invention, such as, for example, a gum, a starch, a sugar, a cellulosic material, an acrylate, or mixtures thereof. . A preferred diluent is microcrystalline cellulose. The compositions may further comprise a disintegrating agent (e.g. croscarmellose sodium) and a lubricant (e.g. magnesium stearate), and may additionally comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant , a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity-increasing agent, a sweetener, a film-forming agent, or any combination thereof. Additionally, the compositions of the present invention may be in the form of controlled release or immediate release formulations.

[0040] For liquid formulations, pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous vehicles include water, aqueous/alcoholic solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish liver oil. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl halide; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and tonicity adjusting agents such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

[0041] In addition, the compositions may further comprise binders (e.g. acacia, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. corn, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycollate, Primogel), buffers (e.g. tris-HCl, acetate, phosphate) of various pHs and ionic strengths, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g. Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers , solubilizing agents (e.g. glycerol), polyethylene glycerol), a glidant (e.g. colloidal silicon dioxide), antioxidants (e.g. ascorbic acid, sodium metabisulfite, hydroxyanisole l butylated), stabilizers (e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosity increasing agents (e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. sucrose, aspartame, citric acid) , flavoring agents (e.g. mint, methyl salicylate, or orange flavoring), preservatives (e.g. Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium sulfate lauryl), flow aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymeric coatings (e.g. e.g. poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.

[0042] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biocompatible, biodegradable polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspension (including liposomes targeted to infect cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example as described in US Patent No. 4,522,811.

[0043] It is especially advantageous to formulate oral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Specifications for the unit dosage forms of the invention are dictated by and directly dependent upon the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and inherent limitations in the art of composing such an active compound for the treatment of subjects.

[0044] Pharmaceutical compositions may be included in a container, pack, or dispenser along with instructions for administration.

[0045] Daily administration may be repeated continuously over a period of several days to several years. Oral treatment can continue for between a week and the patient's life. Preferably administration can take place for five consecutive days after which time the patient can be evaluated to determine if further administration is required. Administration may be continuous or intermittent, for example a treatment for a number of consecutive days followed by a rest period. The compounds of the present invention can be administered intravenously on the first day of treatment, with oral administration on the second day and every consecutive day thereafter.

[0046] The preparation of pharmaceutical compositions containing an active compound is well understood in the art, for example, by mixing, granulating, or tabletting processes. The active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, the active agents are mixed with additives customary for this purpose, such as inert vehicles, stabilizers, or diluents, and converted by customary methods into forms suitable for administration, such as tablets, coated tablets, hard gelatine capsules or soft, aqueous, alcoholic or oily solutions and the like as detailed above.

[0047] The amount of compound administered to the patient is less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of the compound that is administered to the patient is less than the amount that causes a concentration of the compound in the patient's plasma equal to or in excess of the toxic level of the compound. Preferably, the concentration of the compound in the patient's plasma is maintained at about 10 nM. In one configuration, the concentration of the compound in the patient's plasma is maintained at about 25 nM. In one configuration, the concentration of the compound in the patient's plasma is maintained at about 50 nM. In one configuration, the concentration of the compound in the patient's plasma is maintained at about 100 nM. In one configuration, the concentration of the compound in the patient's plasma is maintained at about 500 nM. In one configuration, the concentration of the compound in the patient's plasma is maintained at about 1000 nM. In one configuration, the concentration of the compound in the patient's plasma is maintained at about 2500 nM. In one configuration, the concentration of the compound in the patient's plasma is maintained at about 5000 nM. The optimal amount of the compound to be administered to the patient in the practice of the present invention will depend on the particular compound used and the type of cancer being treated.

Definitions

[0048] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this report and in the claims, unless otherwise limited to specific examples, individually or as part of a larger group.

[0049] An "aliphatic group" or "aliphatic" is a non-aromatic moiety that may be saturated (e.g. single bond) or contain one or more units of unsaturation, e.g. double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen or, optionally, one or more heteroatoms, and may be substituted or unsubstituted. An aliphatic group, when used as a linker, preferably contains from about 1 to about 24 atoms, more preferably from about 4 to about 24 atoms, more preferably from about 4-12 atoms, more typically from about 4-12 atoms. 4 and about 8 atoms. An aliphatic group, when used as a substituent, preferably contains from about 1 to about 24 atoms, more preferably, from about 1 to about 10 atoms, more preferably from about 1-8 atoms, more typically from about 1 to about 6 atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyl, such as polyalkylene glycol, polyamines, and polyimines, for example. Said aliphatic groups may be further substituted. It should be understood that aliphatic groups include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl groups described herein.

[0050] The term "substituted carbonyl" includes compounds and moieties that contain a carbon bonded with a double bond to an oxygen atom, and tautomeric forms thereof. Examples of moieties containing a substituted carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like. The term "carbonyl moieties" refers to groups such as "alkylcarbonyl" groups where an alkyl group is covalently bonded to a carbonyl group, "alkenylcarbonyl" groups, where an alkenyl group is covalently bonded to a carbonyl group, "alkynylcarbonyl" group ' where an alkynyl group is covalently bonded to a carbonyl group, "arylcarbonyl" group where an aryl group is covalently bonded to the carbonyl group. Furthermore, the term also refers to groups where one or more heteroatoms are covalently bonded to the carbonyl moiety. For example, the term includes moieties such as, for example, aminocarbonyl moieties (where a nitrogen atom is attached to the carbon of the carbonyl group, for example an amide).

[0051] The term "acyl" refers to hydrogen, alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups. For example, acyl includes groups such as (C1-C6) alkanoyl, (e.g. formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.), (C3-C6) cycloalkylcarbonyl (e.g., cyclopropylcarbonyl , cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g. pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.), aroyl (e.g. benzoyl) and heteroaroyl (e.g. example, thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl, furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl, benzo[b]thiophenyl-2- carbonyl, etc.). In addition, the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any of the groups described in the respective definitions. When indicated as being "optionally substituted", the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) selected independently from the group of substituents listed below in the definition for "substituted" or the alkyl moiety. , cycloalkyl, heterocycle, aryl and heteroaryl of the acyl group may be substituted as described above in the list of preferred and most preferred substituents, respectively.

[0052] The term "alkyl" embraces linear or branched radicals having one to about 20 carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about eight carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.

[0053] The term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms, or preferably two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about ten and more preferably about two to about eight carbon atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" encompass radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.

[0054] The term "alkynyl" embraces linear or branched radicals having at least one carbon-carbon triple bond of two to about twenty carbon atoms or preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about ten and more preferably two to about eight carbon atoms. Examples of alkynyl radicals include propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl.

[0055] The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0056] The term "cycloalkenyl" embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals which are partially unsaturated carbocyclic radicals that contain two double bonds (which may or may not be conjugated) can be called "cycloalkyldienyl". More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

[0057] The term "alkoxy" embraces linear or branched oxy-containing radicals each having alkyl moieties of one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to about ten and more preferably having one to about eight carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.

[0058] The term "alkoxyalkyl" embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, i.e., to form monoalkoxyalkyl and dialkoxyalkyl radicals.

[0059] The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, such rings may be linked together in a pendant manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

[0060] The terms "heterocyclyl", "heterocycle", "heterocyclic" or "heterocycle" embrace ring-shaped radicals containing saturated, partially unsaturated and unsaturated heteroatoms, which may also be called "heterocyclyl", "heterocycloalkenyl" and " heteroaryl” correspondingly, where the heteroatoms can be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, morpholinyl, etc.); 3- to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg, thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihyrofuran and dihydrothiazole. Heterocyclyl radicals may include a pentavalent nitrogen, as in tetrazolium and pyridinium radicals. The term "heterocycle" also encompasses radicals where heterocyclyl radicals are fused to aryl or cycloalkyl radicals. Examples of bicyclic radicals include benzofuran, benzothiophenes, and the like.

[0061] The term "heteroaryl" embraces unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2 ,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.); unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, e.g. indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g. tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing a sulfur atom, e.g. thienyl, etc.; 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, e.g. oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, e.g. thiazolyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg, benzothiazolyl, benzothiadiazolyl, etc.) and the like.

[0062] The term "heterocycloalkyl" embraces heterocycle substituted alkyl radicals. More preferred heterocycloalkyl radicals are "lower heterocycloalkyl" radicals having one to six carbon atoms in the heterocycle radicals.

[0063] The term "alkylthio" embraces radicals containing a linear or branched alkyl radical of one to about ten carbon atoms bonded to a divalent sulfur atom. Preferred alkylthio radicals have alkyl radicals of one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylthio radicals have alkyl radicals which are "lower alkylthio" radicals having one to about ten carbon atoms. Most preferred are alkylthio radicals having lower alkyl radicals of one to about eight carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.

[0064] The terms "aralkyl" or "arylalkyl" embrace aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.

[0065] The term "aryloxy" embraces aryl radicals bonded by an oxygen atom to other radicals.

[0066] The terms "aralkoxy" or arylalkoxy embrace radicals linked by an oxygen atom to other radicals.

[0067] The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. Preferred aminoalkyl radicals have alkyl radicals having from about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred aminoalkyl radicals are "lower aminoalkyl" which have alkyl radicals having one to about ten carbon atoms. Most preferred are aminoalkyl radicals having lower alkyl radicals having one to eight carbon atoms. Examples of such radicals include aminomethyl, aminoethyl and the like.

[0068] The term "alkylamino" denotes amino groups that are substituted with one or two alkyl radicals. Preferred alkylamino radicals have alkyl radicals having from about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylamino radicals are "lower alkylamino" which have alkyl radicals having one to about ten carbon atoms. Most preferred are alkylamino radicals having lower alkyl radicals having one to about eight carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.

[0069] The term "substituted" refers to the substitution of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, oxo, thioxy, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphoric acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is to be understood that the substituent may be further substituted.

[0070] For simplicity, the chemical moieties that are defined and referred to throughout may be univalent chemical moieties (eg, alkyl, aryl, etc.) or multivalent moieties under appropriate structural circumstances clear to those skilled in the art. For example, an "alkyl" moiety may be referred to as a monovalent radical (e.g., CH3-CH2-), or in other examples, a bivalent linker moiety may be "alkyl", in which case those skilled in the art will understand that the alkyl may be a divalent radical (e.g. -CH2-CH2-), which is equivalent to the term "alkylene". Similarly, in circumstances where divalent moieties are required and are recorded as "alkoxy", "alkylamino", "aryloxy", "alkylthio", "aryl", "heteroaryl", "heterocyclic", "alkyl", "alkenyl" ”, “alkynyl”, “aliphatic”, or “cycloalkyl”, those skilled in the art will understand that the terms “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”, “heterocyclic” , "alkyl", "alkenyl", "alkynyl", "aliphatic", or "cycloalkyl" refer to the corresponding divalent moiety.

[0071] The terms "halogen" or "halo" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.

[0072] As used herein, the term "abnormal proliferation" refers to the abnormal growth of cells.

[0073] The phrase "secondary therapy" encompasses the treatment of a subject with agents that reduce or prevent side effects associated with the combination therapy of the present invention, including, but not limited to, those agents, for example, that reduce the effect. toxicant of anti-cancer drugs, for example, bone resorption inhibitors, cardioprotective agents; prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiation therapy, or operation; or reduce the incidence of infection associated with the administration of myelosuppressive anticancer drugs.

[0074] The term "angiogenesis" as used herein refers to the formation of blood vessels. Specifically, angiogenesis is a multistep process in which endothelial cells focussedly degrade and invade through their own basement membrane, migrate through the interstitial stroma against an angiogenic stimulus, proliferate proximal to the migrating tip, organize into blood vessels, and reconnect. the newly synthesized basement membrane (see Folkman et al., Adv. Cancer Res. Vol. 43, pages 175-203 (1985)). Antiangiogenic agents interfere with this process. Examples of agents that interfere with several of these steps include thrombospondin-1, angiostatin, endostatin, interferon alpha, and compounds such as matrix metalloproteinase (MMP) inhibitors that block the actions of enzymes that cleanse and create pathways for newly formed blood vessels to follow; compounds, such as alpha versus beta 3 inhibitors, that interfere with molecules that blood vessel cells use to cross between a blood vessel of origin and a tumor; agents, such as specific COX-2 inhibitors, that prevent the growth of cells that form new blood vessels, and protein-based compounds that simultaneously interfere with several of these targets.

[0075] The term "apoptosis" as used herein refers to a programmed death of cells as signaled by the nucleus in normally functioning human and animal cells where age or health status and cell condition predominate. An “apoptosis-inducing agent” triggers the process of programmed cell death.

[0076] The term "cancer" as used herein denotes a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue by invasion or by implantation at distant sites by metastases.

[0077] The term "compound" is defined herein to include salts, solvates, hydrates, polymorphs, enantiomers, distereoisomers, racemates and the like of the compound having the formula depicted herein.

[0078] The term “device” refers to any utensil, usually mechanical or electrical, designed to perform a particular function.

[0079] As used herein, the term "dysplasia" refers to an abnormal growth of cells.

[0080] The term "hyperplasia" as used herein refers to a division or overgrowth of cells.

[0081] The phrase an "immunotherapeutic agent" refers to agents used to transfer immunity from an immune donor, for example, another person or an animal, to a host by inoculation. The term encompasses the use of serum or gamma globulin containing preformed antibodies produced by another individual or an animal; non-specific systemic stimulus; adjuvants; active specific immunotherapy; and adoptive immunotherapy. Adoptive immunotherapy refers to the treatment of a disease by a therapy or agents that include inoculation of the host with sensitized lymphocytes, transfer factor, immune RNA, or antibodies into serum or gamma globulin.

[0082] The term “inhibition” in the context of neoplasia, tumor growth or tumor cell growth, can be evaluated by the delayed onset of primary or secondary tumors, the slower development of primary or secondary tumors, the decreased occurrence of primary tumors or secondary, slower or lessened severity of disease side effects, halted tumor growth and tumor regression, among others. At the extreme, complete inhibition is referred to herein as prevention or chemoprevention.

[0083] The term "metastasis" as used herein refers to the migration of cancer cells from the original tumor site through the blood and lymph vessels to produce cancers in other tissues. Metastasis is also the term used for the growth of secondary cancer at a distant site.

[0084] The term “neoplasm,” as used herein, refers to an abnormal mass of tissue that results from excessive cell division. Neoplasms can be benign (non-cancerous) or malignant (cancerous) and can also be called a tumor. The term “neoplasm” is the pathological process that results in tumor formation.

[0085] As used here, the term “precancerous” refers to a condition that is not malignant but is likely to become malignant if left untreated.

[0086] The term “proliferation” refers to cells undergoing mitosis.

[0087] The phrase "HSP90-related disease or disorder" refers to a disease or disorder characterized by inappropriate activity of HSP90 or over-activity of HSP90. Inappropriate activity refers to any of, (i) expression of HSP90 in cells that do not normally express HSP90; (ii) increased expression of HSP90 leading to undesired proliferation, differentiation and/or cell growth; or, (iii) decreased expression of HSP90 leading to undesired reductions in cell proliferation, differentiation and/or growth. HSP90 overactivity refers to the amplification of the gene encoding a particular HSP90 or production of a level of HSP90 activity that may correlate with a disorder of cell proliferation, differentiation, and/or growth (i.e., as the level of HSP90 increases, the severity of one or more of the symptoms of the cellular disorder increases).

[0088] The phrase a "radiotherapeutic agent" refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia.

[0089] The term "recurrence" as used here refers to the return of cancer after a period of remission. This may be due to incomplete removal of cells from the initial cancer and may occur locally (the same site as the initial cancer), regionally (in the vicinity of the initial cancer, possibly in the lymph nodes or tissues), and/or distally as a result of metastasis. .

[0090] The term "treatment" refers to any process, action, application, therapy, or the like, where a mammal, including a human, is subjected to medical assistance with the aim of improving the condition of the mammal, directly or indirectly. .

[0091] The term "vaccine" includes agents that induce the patient's immune system to mount an immune response against the tumor by attacking cells that express tumor-associated antigens (Teas).

[0092] As used herein, the term "effective amount of the compound in question", with respect to the method of treatment subjected, refers to an amount of the compound which, when released as part of the desired dose regimen, produces, for example , a change in the rate of cell proliferation and/or differentiation state and/or survival rate of a cell to a clinically acceptable standard. This amount may alleviate to some extent one or more of the symptoms of a neoplasm disorder, including, but not limited to: 1) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (ie, decrease to a certain extent, preferably, interruption) of cancer cell infiltration into peripheral organs; 4) inhibition (ie, decrease to a certain extent, preferably arrest) of tumor metastasis; 5) inhibition, to a certain extent, of tumor growth; 6) alleviation or reduction to a certain extent to a certain extent in one or more of the symptoms associated with the disorder; and/or 7) alleviation or reduction of side effects associated with the administration of the anti-cancer agents.

[0093] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, response allergy and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M.Berge et al., describe pharmaceutically acceptable salts in detail in "J. Pharmaceutical Sciences", 66: 1-19 (1977). Salts can be prepared in situ during isolation and final purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic or inorganic acid. Examples of pharmaceutically acceptable non-toxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, lactobionic acid or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate salts , glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, alkobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate , pamoate, pectinate, persulfate, 2-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0094] As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that readily decompose in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates.

[0095] The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of accurate medical judgment, suitable for use in contact with the tissues of humans and animals. lower with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. "Prodrug" as used herein means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to a compound of the invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard (Ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (Ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (Ed.) “Design and Application of Prodrugs, Textbook of Drug Design and Development [Prodrug Construction and Application, Drug Design and Development Textbook], chapter 5, 113-191( 1991); Bundgaard et al., “Journal of Drug Deliver Reviews,” 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 and seq. (1988); Higuchi and Stella (Eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa and Joachim Mayer, “Hydrolysis in Drug And Prodrug Metabolism, Chemistry, Biochemistry And Enzymology” John Wiley and Sons, Ltd. (2002).

[0096] As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration, such with sterile pyrogen-free water. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the art, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, brine, Finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils can also be used. The use of such media and agents to pharmaceutically activate substances is well known in the art. Except to the extent that any conventional media or agent is incompatible with the active compound, its use in the compositions is contemplated. Supplementary active compounds may also be incorporated into the compositions.

[0097] As used here, the term “precancerous” refers to a condition that is not malignant but is likely to become malignant if left untreated.

[0098] The term "individual" as used herein refers to an animal. Preferably the animal is a mammal. More preferably the mammal is a human. An individual also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, and the like.

[0099] The compounds of this invention can be modified by attaching appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow for administration by injection, alter metabolism and alter the rate of excretion.

[0100] The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography or recrystallization. As can be appreciated by the skilled artisan, additional methods for synthesizing the compounds of the formulas herein will be apparent to those of ordinary skill in the art. Additionally, the various synthetic steps can be performed in an alternating sequence or in order to provide the desired compounds. Synthetic chemical transformations and protecting group (protection and deprotection) methodologies useful in the synthesis of the compounds described herein are known in the art and include, for example, those as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis [Fieser and Fieser's Reagents for Organic Synthesis], John Wiley and Sons (1994); and L. Paquette, Ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0101] The compounds described here contain one or more asymmetric centers and therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. The present invention is intended to include all possible isomers as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedures described above, or by separating racemic mixtures. Resolution may be performed in the presence of a separating agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Additional details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers and/or cis- and trans isomers. -. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so records; therefore a carbon-carbon double bond or carbon-heteroatom double bond arbitrarily represented herein as trans may be cis, trans, or a mixture of the two in any proportion.

pharmaceutical compositions

[0102] The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.

[0103] As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic encapsulating material or auxiliary formulation, inert solid, semi-solid or liquid filler, diluent of any type. Some examples of materials that serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; cyclodextrins such as alpha (α), beta (β) and gamma (y) cyclodextrins; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth, malt; gelatin; baby powder; excipients such as cocoa butter and wax suppositories; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic brine; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and flavoring agents, preservatives and antioxidants may also be present in the composition at the discretion of the formulator.

[0104] The pharmaceutical compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or carriers. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its form of delivery. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0105] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed, peanut, corn, seed, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol , polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0106] Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known technique using suitable wetting or dispersing agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0107] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. .

[0108] To prolong the effect of a drug, it is often desirable to reduce the rate of absorption of the drug from subcutaneous or intramuscular injection. This may be accompanied by the use of a liquid suspension of a crystalline material or amorphous material with poor water solubility. The rate of absorption of the drug will then depend on its rate of dissolution, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are produced by forming microcapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(ortho-esters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or micro-emulsions that are compatible with body tissue.

[0109] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax that is solid at room temperature but liquid. at body temperature and, therefore, melts in the rectal or vaginal cavity and releases the active compound.

[0110] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, subcrose, glucose , mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as Agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, alcohol cetyl and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium sulfate laurilla, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0111] Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatine capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.

[0112] The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0113] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic formulations, ear drops, ointments, eye powders and solutions are also contemplated as being within the scope of this invention.

[0114] Ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0115] Powders and sprays may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons.

[0116] Transdermal patches have the added advantage of providing the controlled release of a compound into the body. Such dosage forms can be produced by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymeric matrix or gel.

[0117] For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration, for example, inhalation within the respiratory system. Solid or liquid particulate forms of the active compound prepared to practice the present invention include particles of respirable size: that is, particles of a size small enough to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Aerosol delivery of therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example, U.S. Patent No. 5,767,068 to VanDevanter et al., U.S. Patent No. 5,508,269 to Smith et al., and international publication WO 98/43650 by Montgomery, all of which are incorporated herein by reference). A discussion of pulmonary delivery of antibiotics is also found in US Patent No. 6,014,969, incorporated herein by reference.

[0118] By a "therapeutically effective amount" of a compound of the invention is meant an amount of the compound that confers a therapeutic effect on the subject being treated, in a reasonable benefit/risk ratio applicable to any medical treatment.

[0119] The therapeutic effect can be objective (ie measurable by some test or marker) or subjective (ie the subject gives an indication of or feels an effect). An effective amount of the compound described above can range from about 0.1 mg/kg to about 500 mg/kg, preferably from about 1 to about 50 mg/kg. Effective doses will also vary depending on the route of administration, as well as the possibility of co-use with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of accurate medical judgment. The specific therapeutically effective dose level for a particular patient will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and the rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or contemporaneously with the specific compound employed; and similar factors well known in the medical arts.

[0120] The total daily dose of the compounds of this invention administered to a human or other animal in single or divided doses can be in amounts, for example, from 0.01 to 50 mg/kg by body weight or more usually from 0.1 at 25 mg/kg per body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens in accordance with the present invention comprise administering to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.

[0121] Compounds of the formulas described herein may, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg by body weight, alternatively dosages between 1 mg and 1,000 mg/kg dose, every 4 to 120 hours, or as required by the particular drug. The methods herein contemplate administering an effective amount of a compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times a day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with pharmaceutically acceptable excipients or carriers to produce a single dosage form will vary depending on the host treated with the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations may contain from about 20% to about 80% active compound.

[0122] Lower or higher doses than those prescribed here may be required. The specific dosages and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet, time of administration, rate of excretion, combination of drugs, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the physician providing treatment.

[0123] Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of of symptoms, to a level at which the condition of improvement is maintained when symptoms have been relieved to a desired level. Patients may, however, require intermittent treatment on a long-term basis with any recurrence of disease symptoms.

synthetic methods

[0124] The compounds of the invention, or a pharmaceutically acceptable salt thereof, can be prepared by any process known to be applicable for the preparation of chemically related compounds. Suitable processes for producing certain intermediates include, for example, those illustrated in PCT international patent applications WO 02/36075, WO03/037860 and WO 2006/084030. The preparation of said starting materials is described within the appended non-limiting examples. Alternatively the necessary starting materials are obtainable by procedures analogous to those illustrated which are within the ordinary experience of a chemist.

[0125] The compounds and processes of the present invention will be better understood in conjunction with the following representative synthetic schemes, which illustrate the methods by which the compounds of the invention may be prepared, which are intended to be illustrative only and not limiting. of the scope of the invention.

Examples

[0126] The compounds and processes of the present invention will be better understood in conjunction with the following examples, which are intended to be illustrative only and not limiting the scope of the invention. Various changes and modifications to the disclosed configurations will be apparent to those skilled in the art and such changes and modifications, including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of of the invention and the scope of the appended claims.

Example 1: Preparation of 2-(6-bromobenzol[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4- amine (compound 1) Step 1a: Pent-4-in-1-amine (Compound 0102)

[0127] To the solution of compound 0101 (6.0 g, 28.14) in a solvent mixture of methylene chloride and ethanol (10:1, 220 mL) was added hydrazine monohydrate (14.1 g, 281 .4 mmol). The reaction mixture was refluxed for 5 hours and then cooled and filtered. Water (200 mL) was added and the pH adjusted to 2 with 6 N HCl. The mixture was properly stirred and the methylene chloride layer was separated. The aqueous layer was adjusted to pH 13 and extracted with two portions of methylene chloride. The organic phase was collected and evaporated under atmospheric pressure to give the title product 0102 as a brown oil (4.4 g) which was used directly for the next step without further purification. LCMS: 84 [M+1]+.

Step 1b: 2,4-Dichloro-3-nitropyridine (Compound 0109)

[0128] Compound 0108 (10.0 g, 64.0 mmol) was dissolved in POCl 3 (70 mL) and heated overnight at 85°C. Excess POCl3 was evaporated at atmospheric pressure. The residue was neutralized (pH 7) with saturated NaHCO3. The precipitate was filtered and dried to give the title compound 0109 as a yellow solid (9.95 g, 80.5%): 1H NMR (CDCl 3 ) δ 7.47 (d, J = 5.7 Hz, 1H), 8.44 (d , J = 5.1 Hz, 1H).

Step 1c: 2-Chloro-N4-(pent-4-ynyl)pyridine-3,4-diamine (Compound 0111)

[0129] To a solution of compound 0109 (8.9 g, 46.12 mmol) in DMF (177 mL) was added to compound 0102 (5.8 g) and triethylamino (5.6 g, 55.34 mmol) . The reaction mixture was stirred at room temperature for 4 hours. The mixture was evaporated to remove DMF and purified by silica gel column chromatography. (EtOAc/petroleum = 10:1) to obtain the title compound 0110 as a yellow solid (8.6 g, 77.8%): LCMS: 240 [M+1]+; 1H NMR (CDCl3) δ 1.89 (m, 2H), 2.06 (t, J = 2.7 Hz, 1H), 2.35 (m, 2H), 3.45 (m, 2H), 6.63 (s, 1H), 6.69 (d, J = 6.3 Hz, 1H), 8.04 (d, J = 6.3 Hz, 1H).

Step 1d: 2-Chloro-N4-(pent-4-ynyl)pyridine-3,4-diamine (Compound 0111)

[0130] To a solution of compound 0110 (8.6 g, 35.88 mmol) in methanol (430 mL) was added water (43 mL0, iron powder (20.04 g) and concentrated HCl solutions (3 mL The reaction mixture was stirred at room temperature for 30 minutes and then heated to reflux overnight. The mixture was adjusted to pH 11 with 6N NaOH and filtered and washed with methanol (50 mL). The filtrate was concentrated and purified by silica gel column chromatography (5.5 g, 73.1%). LCMS: 210 [M+1]+; 1H NMR (DMSO-d6) δ 1.75 (m, 2H), 2.29 (m, 2H), 2.83 (t, J = 2.7 Hz, 1H), 3.19 (m, 2H), 4.78 (s, 2H) 5.73 (t, J = 5.1 Hz, 1H) 6.41 (d, J = 5.4 Hz, 1H), 7.41 (d , J = 5.1 Hz, 1H).

Step 1e: 4-Chloro-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione (Compound 0112)

[0131] A mixture of compound 0111 (3.54 g, 17.36 mmol), carbon disulfide (6.6 g, 86.8 mmol), potassium hydroxide (4.87 g, 86.8 mmol) in ethanol (22 mL), and water (3.3 mL) was heated to reflux overnight. The mixture was cooled to room temperature and water (60 mL) was added. The mixture was adjusted to pH 7 with acetic acid and then extracted with methylene chloride (100 mL x 2). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (5:1 EtOAc/petroleum) to obtain the title compound 0112 as a pale yellow solid (3.9 g, 89%): LCMS: 252 [ M+1]+; 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.26 (m, 1H), 2.83 (t, J = 2.7 Hz, 2H), 4.28 (t, J = 7.5 Hz, 2H), 7.53 (d, J = 5.1 Hz, 1H), 8.15 (d, J = 5.4 Hz, 1H), 13.64 (s, 1H).

Step 1f: 4-Amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione (Compound 0113)

[0132] A mixture of compound 0112 (1.0 g, 4.0 mmol) and sodium starch (3.0 g, 77.0 mmol) in 25 mL of liquid ammonia was loaded into an air-free sealed tube and stirred. at 0°C for 30 hours. The tube was opened after cooling to -40°C and ethanol was carefully added to terminate the reaction until no gas was produced. 200 ml of water was added and the mixture adjusted to pH 7 with acetic acid and then extracted with two portions of methylene chloride. The combined organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (methylene chloride/methanol = 50:1) to obtain the title compound 0113 as a gray solid (497 mg, 54%). LCMS: 233 [M+1]+; 1H NMR (DMSO-d6) δ 1.89 (m, 2H), 2.23 (m, 2H), 2.86 (s, 1H), 4.19 (t, J = 7.5 Hz, 2H), 6.12 (s, 2H), 6.75 ( d, J = 5.4 Hz, 1H), 7.74 (d, J = 5.4 Hz, 1H), 12.50 (s, 1H).

Step 1g: 5-Bromo-6-iodobenzo[d][1,3]dioxol (Compound 0107-1)

[0133] A solution of compound 0106 (10.0 g, 50.0 mmol), anhydrous acetonitrile (150 mL), TFA (11.4 g, 100.00 mmol) and NIS (33.7 g, 150.0 mmol) was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum) to give the title compound 0107-1 as a white solid (18.5 g, 91%): 1H NMR ( DMSO-d6) δ 5.99 (s, 2H), 7.10 (s, 1H), 7.26 (s, 1H).

Step 1h: 2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine ( Compound 1)

[0134] A mixture of compound 0113 (150.0 mg, 0.65 mmol), 5-Obromo-6-iodobenzo[d][1,3]dioxol (Compound 0107) (633.0 mg, 1.94 mmol ), neocuproin hydrate (13.0 mg, 0.065 mmol), CuI (12.0 mg, 0.065 mmol) and NaOt-Bu (124.0 mg, 1.29 mmol) in anhydrous DMF (6, mL) was stirred for 24 hours at 110°C (oil bath) under nitrogen atmosphere. The solvent was removed under high vacuum and the crude purified by silica gel column chromatography (CH 2 Cl 2 /MeOH = 100/1 to obtain the title compound 1 as an orange solid (117 mg, 42%): m.p. 52.9~ 60.5oC,n LCMS: 432 [M+1]+; 1H NMR (DMSO-d6) δ 1.81 (m, 2H), 2.19 (m, 2H), 2.83 (t, J = 2.4 Hz, 1H), 4.25 ( t, J = 7.2 Hz, 2H), 6.07 (s, 2H), 6.38 (s, 2H), 6.71 (s, 1H), 6.83 (d, J = 6.0 Hz, 1H,), 7.35 (s, 1H), 7.72 (d, J = 5.4 Hz, 1H).

Example 2: Preparation of 2-(6-Chlorobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4- amine (Compound 2) Step 2a: 5-Chloro-6-iodobenzo[d][1,3]dioxol (Compound 0107)

[0135] A solution of compound 0106 92.0 g, 12.77 mmol), acetonitrile (80 mL), TFA (2.9 g) and NIS (8.6 g, 38.3 mmol) was stirred at room temperature. for 24 hours. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (petroleum) to give the title compound 0107 as a white solid (3.27 g, 90.6%) (3.27 g , 90.6%): 1H NMR (DMSO-d6) δ 6.10 (s, 2H), 7.25 (s, 1H), 7.45 (s, 1H).

Step 2b: 2-(6-Chlorobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine ( Compound 2)

[0136] A mixture of compound 0113 (100 mg, 0.43 mmol), 5-chloro-6-iodobenzo[d][1,3]dioxol (compound 0107) (364 mg, 1.29 mmol), hydrate of neocuproin (9mg, 0.043mmol), CuI (8mg, 0.043mmol) and non-t-Bu (83mg, 0.86mmol) in anhydrous DMF (4.6mL) was stirred for 24 hours at 110°C (oil bath) under nitrogen atmosphere. The solvent was removed under high vacuum and the crude purified by silica gel column chromatography (CH 2 Cl 2 /MeOH at 100/1) to obtain the title compound 1 as a pale yellow solid (52 mg, 31%): LCMS : 387 [M+1]+; 1H NMR (DMSO-d6) δ 1.81 (m, 2H), 2.19 (m, 2H), 2.85 (t, 1H, J = 2.4 Hz), 4.25 (t, 2H, J = 7.2 Hz), 6.09 (s, 2H), 6.37 (s, 2H), 6.76 (s, 1H), 6.82 (d, 1H, J = 5.7 Hz), 7.25 (s, 1H), 7.71 (d, 1H, J = 5.7 Hz).

Example 3: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4- amine (Compound 3) Step 3a: 5,6-Diiodobenzo[d][1,3]dioxol (Compound 0107)

[0137] A solution of compound 0106 (1.0g, 8.19 mmol), acetonitrile (51 mL), TFA (1.867 g) and NIS (4.05 g, 18.02 mmol) was stirred at room temperature for 24 hours. hours. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (petroleum) to give the title compound 0107 as a white solid (1.48 g, 48%):1H NMR (DMSO -d6) δ 6.05 (s, 2H), 7.46 (s, 2H).

Step 3b: 2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine ( Compound 3)

[0138] A mixture of compound 0113 (200 mg, 0.86 mmol), 5,6-diiodobenzo[d][1,3]dioxol (Compound 0107) (483 mg, 1.29 mmol), neocuproine hydrate ( 18 mg, 0.086 mmol), CuI (16 mg, 0.086 mmol) and non-t-Bu (83 mg, 0.86 mmol) in anhydrous DMF (8 mL) was stirred for 24 hours at 110° (oil bath) under nitrogen atmosphere. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH at 100/1) to obtain the title compound 3 as a white solid (82 mg, 20%): LCMS : 479 [M+1]+; 1H NMR (DMSO-d6) δ 1.81 (m, 2H), 2.20 (m, 2H), 2.84 (t, 1H, J = 2.4 Hz), 4.23 (t, 2H, J = 7.2 Hz), 6.05 (s, 2H), 6.37 (s, 2H), 6.69 (s, 1H), 6.82 (d, 1H, J = 6.0 Hz), 7.48 (s, 1H), 7.72 (d, 1H, J = 5.7 Hz).

Example 3(Method 2): Preparation of 2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c] pyridin-4-amine (Compound 3) Step 3a': 2-Chloro-N-(4-methoxybenzyl)-3-nitropyridin-4-amine (Compound 0201)

[0139] To a solution of compound 0109 (1 g, 5.18 mmol) in DMF (8.6 mL) was added (4-methoxyphenyl)methanamine (0.71 g, 5.18 mmol) and triethylamine (0.644 mL). ). The solution was stirred at room temperature for 2 hours. The mixture was evaporated to remove DMF. The resulting mixture was purified by silica gel column chromatography (10:1 EtOAc/petroleum) to obtain the title compound 0201 as a white solid (1.32 g, 87%): %): LCMS: 294 [M +1]+; 1H NMR (DMSO-d6) δ 3.72 (s, 3H), 4.40 (d, 2H, J = 6.3 Hz), 6.81 (d, 1H, J = 5.7 Hz), 6.91 (d, 2H, J = 9.0 Hz) , 7.25 (d, 2H, J = 8.4 Hz), 7.95 (d, 1H, J = 5.4 Hz), 8.02 (t, 1H, J = 5.7 Hz).

Step 3b': 2-Chloro-N4-(4-methoxybenzyl)pyridine-3,4-diamine (Compound 0202)

[0140] To a mixture of compound 0201 (1.32 g, 4.49 mmol) in methanol (66 mL) and water (6.6 mL) was added iron powder 92.51 g, 44.9 mmol) and a concentrated HCl (1 mL). The mixture was stirred at room temperature for 30 minutes, then refluxed overnight. The mixture was adjusted to pH 11 with 6N NaOH and filtered. The precipitate was washed with methanol (10 ml). The combined filtrate and wash solution were concentrated and purified on silica gel column chromatography (2:1 EtOAc/petroleum) to obtain the title compound 0202 as a pale green solid (712 mg, 60%): LCMS: 264 [M+1]+; 1H NMR (DMSO-d6) δ 3.73 (s, 3H), 4.31 (d, 2H, J = 5.7 Hz), 4.81 (s, 2H), 6.33 (m, 2H), 6.90 (d, 2H, J = 8.7 Hz), 7.26 (d, 2H, J = 9.0 Hz), 7.34 (d, 1H, J = 5.1 Hz).

Step 3c' : 4-Chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione (Compound 0203)

[0141] A mixture of 0202 (2 g, 7.6 mmol), carbon disulfide (2.88 g, 37.9 mmol), potassium hydroxide (2.112 g, 37.9 mmol) in ethanol. (11.5 mL) and water (1.5 mL) was heated at reflux overnight. Water (100 mL was added after the mixture was allowed to cool to room temperature. The mixture was adjusted to pH 7 with acetic acid and then extracted with two portions of methylene chloride. The organic layer was collected and concentrated under pressure. reduced to leave a residue which was purified by silica gel column chromatography (5:1 EtOAc/petroleum) to obtain the title compound 0203 as a white solid (2 g, 86%): LCMS: 306 [M]+ ; 1H NMR (DMSO-d6) δ 3.68 (s, 3H), 6.41 (s, 2H), 6.86 (d, 2H, J = 8.7 Hz), 7.36 (m, 3H), 8.07 (d, 1H, J = 5.4 Hz), 13.74 (s, 1H).

Step 3d': 4-Amino-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione (Compound 0204)

[0142] A mixture of 0203 (1 g, 3.25 mmol) and sodium amide (3g, 77 mmol) in 25 mL of liquid ammonia was loaded into an air-free sealed tube. The mixture was then stirred at room temperature for 30 hours. The mixture was cooled to -40°C and then the tube was opened. Ethanol was carefully added to terminate the reaction until no gas was produced. Water (200 mL) was added and the mixture was adjusted to pH 7 with acetic acid. The resulting solid was filtered to obtain the crude product which was purified by silica gel column chromatography (50:1 methylene chloride/methanol) to obtain the title compound 0204 as a white solid (718 mg, 77%): LCMS: 287 [M]+; 1H NMR (DMSO-d6) δ 3.68 (s, 3H), 5.31 (s, 2H), 6.06 (s, 2H), 6.59 (d, 1H, J = 6.3 Hz), 6.85 (d, 2H, J = 9.0 Hz), 7.33 (d, 2H, J = 8.4 Hz), 7.64 (d, 1H, J = 5.7 Hz), 12.53 (s, 1H).

Step 3e': 2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205-3).

[0143] A mixture of 0204 (725 mg, 2.53 mmol), 5,6-diidobenzo[d][1,3]dioxol (0107) (1.189 g, 5.06 mmol), neocuproine hydrate (53 mg , 0.253 mmol), CuI (48 mg, 0.253 mmol) and NaOt-Bu (365 mg, 3.80 mmol) in anhydrous DMF (32 mL) was stirred for 24 hours at 110 °C (oil bath) under an atmosphere of nitrogen. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (100/1 CH 2 Cl 2 /MeOH) to obtain the title compound 0205-3 as a brown solid (734 mg, 55%): LCMS : 533 [M+1]+; 1H NMR (DMSO-d6) δ 3.69 (s, 3H), 5.35 (s, 2H), 6.01 (s, 2H), 6.47 (s, 1H), 6.80 (d, 2H, J = 9.0 Hz), 7.06 ( d, 2H, J = 8.7 Hz), 7.41 (s, 1H).

Step 3f': 2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-3)

[0144] A solution of compound 0205-3 (730 mg, 1.37 mmol) in TFA (4.8 mL) was stirred for 2 hours at 80°C. The TFA was then evaporated and the resulting oil was adjusted to pH 7 with saturated NaHCO3. The resulting precipitate was collected by filtration and further purified by silica gel column chromatography (30/1 CH 2 Cl 2 /MeOH) to obtain the title compound 0206-3 as a yellow solid (526 mg, 93%): LCMS: 413 [M+1]+; 1H NMR (DMSO-d6) δ 6.09 (s, 2H), 6.73 (m, 3H), 7.03 (s, 1H), 7.52 (m, 2H), 12.45 (s, 1H).

Step 3g': 2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 3)

[0145] A mixture of 0206-391 g, 2.426 mmol), 5-chloropent-1-yne (373 mg, 3.639 mmol) and Cs2CO3 (1.34 g, 4.124 mmol) in DMF (35 mL) was stirred at 85°C for 4 hours. DMF was evaporated in vacuo, and the residue was purified by silica gel column chromatography (100:1 methylene chloride/methanol) to give the title compound 3 as a white solid (564 mg, 49%): m. P. 142 ~ 145 oC. 479 [M+1]+; 1H NMR (DMSO-d6) δ 1.81 (m, 2H), 2.20 (m, 2H), 2.85 (t, 1H, J = 2.7 Hz), 4.23 (t, 2H, J = 7.2 Hz), 6.05 (s, 2H), 6.36 (s, 2H), 6.68 (s, 1H), 6.81 (d, 1H, J = 6.0 Hz), 7.48 (s, 1H), 7.72 (d, 1H, J = 5.7 Hz).

Example 4: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-pentyl-1H-imidazo[4,5-c]pyridin-4-amine (Compound 4)

[0146] A mixture of compound 0206 (200mg, 0.485mmol), 1-bromopentane (110mg, 0.728mmol) and CS2CO3 (268mg, 0.825mmol) in DMF (7ml) was stirred at 85°C for 2 hours . DMF was evaporated in vacuo and the residue was purified by silica gel column chromatography (100:1 methylene chloride/mentethanol) to give the title compound 4 as a white solid (40 mg, 17%): m. P. 155 ~ 160 oC. LCMS: 483 [M+1]+; 1H NMR (DMSO-d6) δ 0.783 (t, 3H, J = 6.6 Hz), 1.22 (m, 4H), 1.58 (m, 2H), 4.15 (t, 2H, J = 7.2 Hz), 6.04 (s, 2H), 6.39 (s, 2H), 6.66 (s, 1H), 6.79 (d, 1H, J = 5.7 Hz), 7.49 (s, 1H), 7.71 (d, 1H, J = 6.0 Hz).

Example 5: Preparation of 2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5- c]pyridin-4-amine (Compound 7) Step 5a: 6,7-Diiodo-2,3-dihydrobenzo[b][1,4]dioxin (Compound 0107-7)

[0147] To a solution of compound 0106 (R = H, n = 1) (2 g, 14.7 mmol) in acetonitrile (60 mL) was added NIS (9.92 g, 44.1 mmol) followed by CF3COOH (3.35 g, 29.4 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel column chromatography (Petroleum Ether) to provide the title compound 0107-7 as a white solid (0.7 g, 12%): 1H NMR (DMSO-d6) δ 4.21 (s, 4H), 7.34 (s, 2H).

Step 5b: 2-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c] pyridin-4-amine (Compound 7)

[0148] A mixture of compound 0113 (150 mg, 0.65 mmol), 6,7-diiodo-2,3-dihydrobenzo[b](1,4]dioxin (0107-7) (Compound 0107) (500 mg , 1.29 mmol), Na)t-Bu (93 mg, 0.97 mmol), neocuproine hydrate (13 mg, 0.065 mmol) and CuI (12 mg, 0.065 mmol) in dry DMF (6 mL) was stirred at 110°C overnight. The mixture was concentrated and purified first by silica gel column chromatography (CH2Cl2/MeOH=100/1) and followed by HPLC preparation to give the title compound 7 as a white solid (45 mg, 14%): m.p. 110-118 oC 1H NMR (DMSO-d6) δ 1.88 (m, 2H), 2.25 (m, 2H), 2.85 (t, J = 2.9 Hz, 1H), 4.24 (m, 4H), 4.36 (t, J = 6.9 Hz, 2H), 6.92 (s, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.44 (s, 1H), 7.76 (d, J = 6.6 Hz, 1H), 8.47 (s, 2H ), 01.13

Example 6: Preparation of 2-(2,3-Dihydrobenzofuran-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 9) Step 6a: 4-Amino-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione (Compound 0205-9)

[0149] A mixture of compound 0204 (1.0g, 3.5mmol), 5-iodo-2,3-dihydrobenzofuran (0.86g, 3.5mmol), neocruproin hydrate (74mg, 0.35mmol), CuI (67 mg, 0.35 mmol) and NaOt-Bu (403 mg, 4.2 mmol) in anhydrous DMF (20 mL) was stirred for 24 hours at 110°C (oil bath) under nitrogen atmosphere. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH2Cl2/MeOH=50/1) to give the title compound 0205-9 as a yellow solid (0.38 g, 27%): LCMS: 405 [M+1]+.

Step 6b: 2-(2,3-Dihydrobenzofuran-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-9)

[0150] A mixture of compound 0205-9 (370 mg, 0.915 mmol) and trifluoroacetic acid (10 mL) was stirred at reflux for 5 hours. The solvent was removed and the residue suspended in saturated aqueous NaHCO3 solution. The resulting solid was collected and dried to give the title compound 0206-9 as a yellow solid (210 mg, 81%): LCMS: 285 [M+1]+. (210 mg, 81%): LCMS: 285 [M+1]+.

Step 6c: 2-(2,3-Dihydrobenzofuran-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 9)

[0151] A mixture of compound 0206-9 (204mg, 0.72mmol), CS2CO3 (469mg, 1.44mmol), 5-chloropent-1-yne (111mg, 1.08mol) and anhydrous DMF (5mL ) was stirred for 2 hours at 80°C. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH=100/1) to give the title compound 9 as a pale yellow solid (41 mg, 16%): m.p. 150~157°C, LCMS: 351 [M+1]+. 1H NMR (DMSO-d6δ 1.70) (m, 2H), 2.17 (m, 2H), 2.87 (t, J = 2.7 Hz, 1H), 3.14 (t, J = 8.7 Hz, 2H), 4.22 (t, J = 7.5 Hz, 2H), 4.52 (t, J = 8.7 Hz, 2H), 6.31 (s, 2H), 6.77 (m, 2H), 7.20 (dd, J1 = 1.8 Hz, J2 = 8.1 Hz, 1H), 7.33 (s, 1H), 7.65 (d, J = 4.2 Hz, 1H).

Example 7: Preparation of 2-(Benzofuran-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 10) Step 7a: 2-(Benzofuran-5-ylthio)-1-(4-methoxyenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205-10)

[0152] A mixture of compound 0204 (1.0, 3.5mmol), 5-iodobenzofuran (1.2g, 4.92mmol), neocuproine hydrate (73mg, 0.35mmol, CuI (67mg, 0.35 mmol) and non-t-Bu (403 mg, 4.2mmol) in anhydrous DMF (20 mL) was stirred for 24 hours at 110°C (oil bath) under nitrogen atmosphere. high vacuum and the crude product was purified by silica gel column chromatography (CH2Cl2/MeOH=50/1) to give the title compound 0205-10 as a yellow solid (0.44 g, 31%): LCMS: 403 [M +1]+.

Step 7b: 2-(Benzofuran-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-10)

[0153] A mixture of compound 0205-10 (430mg, 1.07mmol) and trifluoroacetic acid (10ml) was stirred under reflux for 5 hours. The solvent was removed and the residue suspended in saturated aqueous NaHCO3 solution. The resulting solid was collected and dried to give the title compound 0206-10 as a yellow solid (270mg, 89%): LCMS: 283 [M+1]+.

Step 7c: 2-(Benzofuran-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 10)

[0154] A mixture of compound 0206-10 (270 mg, 0.96 mmol), Cs 2 CO 3 (623 mg, 1.91 mmol), 5-chloropent-1-yne (147 mg, 1.44 mol) and anhydrous DMF (10 mL) was stirred for 2 hours at 80°C. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH=100/1) to give the title compound 10 as a pale yellow solid (21 mg, 6%). LCMS: 349 [M+1]+. 1H NMR (DMSO-d6δ 1.73 (m, 2H), 2.17 (m, 2H), 2.87) (t, J = 2.4 Hz, 1H), 4.25 (t, J = 7.5 Hz, 2H), 6.32 (s, 2H ), 6.78 (d, J = 5.7 Hz, 1H), 6.96 (d, J = 1.5 Hz, 1H), 7.35 (dd, J1 = 1.8 Hz, J2 = 8.7 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 5.4 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H).

Example 8: Preparation of 2-(3-Methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 11)

[0155] A mixture of compound 0113 (300mg, 1.29mmol), 1-iodo-3-methoxybenzene (0103)(907mg, 3.87mmol), neocuproine hydrate (27mg, 0.129mmol), CuI (25mg, 0.129 mmol) and NaOt-Bu (248 mg, 2.58) mmol) in anhydrous DMF (12 mL) was stirred for 24 hours at 110°C (oil bath) under nitrogen atmosphere. The solvent was removed under high vacuum and the crude product was purified by silica gel chromatography (CH2Cl2/MeOH = 100/1) to obtain the crude compound which was purified by HPLC preparation to give the title product 11 as a white solid. (190 mg, 43.5%): m.p. 139.2~140.6 oC, LCMS: 339 [M+1]+; 1H NMR (DMSO-d6) δ 1.74 (m, 2H), 2.16 (m, 2H), 2.85 (t, J = 2.7 Hz, 1H), 3.72 (s, 3H), 4.24 (t, J = 7.5 Hz, 2H), 6.39 (s, 2H), 6.85 (m, 4H), 7.27 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 6.0 Hz, 1H).

Example 9: Preparation of 2-(2-iodo-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 12) Step 9a: 1,2-Diiodo-4-methoxybenzene (Compound 0104-12)

[0156] A mixture of compound 103 (2.0g, 8.5mmol), TFA (1.94g) and NIS (5.74g, 25.5mmol) in acetonitrile (60ml) was stirred at room temperature for 24 hours. hours. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (petroleum ether) to give the title compound 104-12 as a colored liquid (1.2 g, 38%). 1H NMR (DMSO-d6) δ 3.75 (s, 3H), 6.77(m, 1H), 7.49 (d, J = 2.7 Hz, 1H), 7.760 (d, J = 8.7 Hz, 1H).

Step 9b: 2-(2-Iodo-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 12)

[0157] A mixture of compound 0113 (230.0mg, 0.99mmol), compound 104-12 (535.0mg, 1.49mmol), neocuproine hydrate (21.0mg, 0.10mmol), CuI (19 .0mg, 0.10mmol) and NaOt-Bu 995.0mg, 1.0mmol) in anhydrous DMF (.2mL) was stirred for 24 hours at 110°C (oil bath) under nitrogen atmosphere. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH= 100/1) to obtain the title compound 12 as a white solid (75 mg, 16.3%): m.p. 114.5~115.2 oC, LCMS: 465 [M+1]+; 1H NMR (DMSO-d6) δ 1.80 (m, 2H), 2.17 (m, 2H), 2.81 (t, J = 2.1 Hz, 1H), 3.59 (s, 3H), 4.24 (t, J = 7.2 Hz, 2H), 6.26 (d, J = 2.4 Hz, 1H) 6.45 (s, 2H), 6.68 (m 1H), 6.84 (d, J = 5.7 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H) , 7.77 (d, J = 8.7 Hz, 1H).

Example 10: Preparation of 2-(2-bromo-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 13) Step 10a: 1-Bromo-2-iodo-4-methoxybenzene (Compound 0104-13)

[0158] Bromine (0.206mL, 4.0mmol) was added dropwise into a solution of compound 0103 (1.0g, 23.20mmol) in acetic acid (4.5mL) with constant stirring overnight. Water (15 mL) was then added to the reaction mixture, and the product was extracted into hexane (3 x 7.5 mL). The combined organic layers were washed with 5% sodium sulfide (7.5mL) and brine &.5mL), dried over magnesium sulfide, filtered and concentrated to separate a fatty solid which was purified by silica gel chromatography (petroleum ) to give the title product 0104-13 as a colored oil (0.5 g, 37%): 1H NMR (CDCl3) δ 3.769 (s, 3H), 6.77 (dd, 1H, J1 = 3.0 Hz, J2 = 8.7 Hz ), 7.39 (d, 1H, J=3.0 Hz), 7.47 (d, 1H, J=9.0 Hz).

Step 10b: 2-(2-Bromo-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 13)

[0159] A mixture of compound 0113 (174mg, 0.75mmol), compound 0104-13 (469mg, 1.5mmol), neocuproine hydrate (16mg, 0.075mmol), CuI (14mg, 0.075mmol), and NaOt-Bu (96 mg, 1.0 mmol) in anhydrous DMF (8 mL) was stirred for 24 hours at 110°C (oil bath) under nitrogen atmosphere. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH at 100/1) to obtain the title compound 13 as a yellow solid (60 mg, 19%): LCMS: 417 [M+1]+; 1H NMR (DMSO-d6) δ 1.88 (m, 2H), 2.23 (m, 2H), 2.81 (t, 1H, J = 2.4 Hz), 3.68 (s, 3H), 4.39 (t, 2H, J = 7.2 Hz), 6.71 (d, 1H, J = 2.7 Hz), 6.91 (dd, 1H, J1 = 2.7 Hz, J2 = 9.3 Hz), 7.31 (d, 1H, J = 6.9 Hz), 7.65 (d, 1H, J = 9.0 Hz), 7.78 (d, 1H, J = 7.2 Hz), 8.63 (s, 2H), 13.248 (s, 1H).

Example 11: Preparation of 2-(2-Chloro-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 14) Step 11a: 1-Chloro-2-iodo-4-methoxybenzene (Compound 0104-14)

[0160] A solution of 0103 (1g, 4.27 mmol) and NCS (2.25g, 17.09 mmol) in anhydrous DMF (24 mL) was stirred at room temperature for 2.5 hours. After the reaction, the solvent was removed and the crude product was purified by silica gel column purification (petroleum) to give crude product 0104-14 as a colored oil (440 mg, 38%): 1H NMR (DMSO- d6) δ 3.76 (s, 3H), 7.00 (dd, 1H, J1 = 2.7 Hz, J2 = 8.4 Hz), 7.47 (m, 2H).

Step 11b: 2-(2-Chloro-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 14)

[0161] A mixture of compound 0113 (150mg, 0.646mmol), compound 0104-14 (260mg, 0.969mmol), neocuproine hydrate (13mg, 0.065mmol), CuI (12mg, 0.065mmol) and NaOt-Bu (62 mg, 0.646 mmol) in anhydrous DMF (6 mL) was stirred for 24 hours at 110°C (oil bath) under nitrogen atmosphere. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH at 100/1) to obtain the title compound 14 as a white solid (25 mg, 10%). LCMS: 373 [M+1]+; 1H NMR (DMSO-d6) δ 1.80 (m, 2H), 2.16 (m, 2H), 2.83 (s, 1H), 3.62 (s, 3H), 4.26 (t, 2H, J = 7.2 Hz), 6.38 ( d, 1H, J = 2.1 Hz), 6.48 (s, 2H), 6.85 (d 1H, J = 6.6 Hz), 6.91 (dd, 1H, J1 = 1.8 Hz, J2 = 7.8 Hz), 7.48 (d, 1H , J = 9.9 Hz), 7.74 (d, 1H, J = 5.7 Hz).

Example 12: Preparation of 2-(2-iodo-4,5-dimethoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 15) Step 12a: 1,2-Diiodo-4,5-dimethoxybenzene (Compound 0104-15)

[0162] To a solution of 1,2-dimethoxybenzene (2g, 14.5mmol) in anhydrous DMF (60mL) was added NCS (9.67g, 43.4mmol) followed by trifluoroacetic acid (3.3g, 28.9 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated and purified by silica gel column chromatography (petroleum ether) to provide the title compound 0104-15 as a white solid (1.9 g, 34%): 1H NMR (DMSO-d6) δ 3.71 (s, 6H), 7.31 (s, 2H).

Step 12b: 2-(2-Iodo-4,5-dimethoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 15)

[0163] A mixture of 0113 (150mg, 0.65mmol), compound 0104-15 (503mg, 1.29mmol), NaOt-Bu (93mg, 0.97mmol), neocuproine hydrate (13mg, 0.065 mmol), and CuI 912 mg, 0.065 mmol) in dry DMF (6 mL) was stirred at 100°C overnight. The mixture was concentrated and first purified by silica gel column chromatography (gel (CH2Cl2/MeOH=100/1) and then by HPLC preparation to give the title product 15 as a white solid (40 mg, 13%): m.p. 134-140 °C. 1H NMR (DMSO-d6) δ 1.88 (m, 2H), 2.26 (m, 2H), 2.86 (t, J = 2.4 Hz, 1H), 3.67 (s, 3H), 3.80 (s, 3H), 4.37 (t, J = 7.4 Hz, 2H), 7.13 (s, 1H), 7.29 (d, J = 6.9 Hz, 1H), 7.44 (s, 1H), 7.75 (d, J = 6.3 Hz, 1H), 8.42 (s, 2H), 13.13 (s, 1H).

Example 13: Preparation of 4-(4-amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)-5-iodobenzene-1,2-diol (Compound 16)

[0164] To a solution of compound 3 (120 mg, 0.251 mmol) in dichloromethane (24 mL) was added dropwise to a solution of BCl 3 in dichloromethane (0.755 mL, 1M) at room temperature under nitrogen. The mixture was stirred for 30 minutes and methanol (50 ml) was stirred. The mixture was heated at reflux temperature for 1 hour. The reaction was evaporated and the resulting residue was purified by pre-HPLC to obtain the title compound 16 as a white solid (35 mg, 30%): m.p. 107 ~115 oC. LCMS: 467 [M+1]+; 1H NMR (DMSO-d6) δ 1.88 (m, 2H), 2.25 (m, 2H), 2.84 (t, 1H, J = 2.1 Hz), 4.33 (t, 2H, J = 6.6 Hz), 6.81 (s, 1H), 7.27 (m, 2H), 7.75 (d, 1H, J = 7.2 Hz), 8.48 (s, 2H), 9.56 (s, 1H), 9.82 (s, 1H), 13.16 (s, 1H).

Example 14: Preparation of 2-(5-Methoxy-2-nitrophenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 17)

[0165] A mixture of compound 0113 (150mg, 0.646mmol), 1-iodo-5-methoxy-2-nitrobenzene (199mg, 0.713mmol), neocuproine hydrate 913mg, 0.065mmol 0 , CuI (12mg, 0.065 mmol) and NaOt-Bu (62mg, 0.646 mmol) in anhydrous DMF (6 mL) was stirred for 24 hours at 110°C (oil bath) under nitrogen atmosphere. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH at 100/1) to obtain the target compound 17 as a pale yellow solid (60 mg, 24%): LCMS: 384 [M+1]+; 1H NMR (DMSO-d6) δ 1.77 (m, 2H), 2.14 (m, 2H), 2.73 (t, 1H, J = 2.4 Hz), 3.69 (s, 3H), 4.24 (t, 2H, J = 6.9 Hz), 6.04 (d, 1H, J = 2.4 Hz), 6.63 (s, 2H), 6.88 (d, 1H, J = 6.0 Hz), 7.07 (dd, 1H, J1 = 2.4 Hz, J2 = 9.3 Hz), 7.78 (d, 1H, J = 6.0 Hz), 8.37 (d, 1H, J = 9.3 Hz).

Example 15: Preparation of 2-(4-amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)-4-methoxybenzonitrile (Compound 18)

[0166] Title compound 18 was prepared as a white solid (25mg, 11%) from compound 0113 (150mg, 0.646mmol0, 2-iodo-4-methoxybenzonitrile (251mg, 0.969mmol), neocuproine hydrate (13mg, 0.0646mmol), CuI (12mg, 0.0646mmol) and NaOt-Bu (62mg, 0.0646mmol) in anhydrous DMF (6mL) using a procedure similar to that described for compound 17 (Example 14): LCMS: 364 [M+1]+; 1H NMR (DMSO-d6) δ 1.84 (m, 2H), 2.20 (m, 2H), 2.83 (t, 1H, J = 2.7 Hz), 3.76 (s 3H), 4.29 (t, 2H, J = 7.5 Hz), 6.41 (s, 2H), 6.77 (s, 2H J = 2.4 Hz), 6.86 (m, 1H), 7.08 (dd, 1H, J1 = 2.4 Hz , J2 = 9.0 Hz), 7.75 (m, 1H), 7.90 (d, 1H, J = 8.1 Hz).

Example 16: Preparation of 1-(2-(4-amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)-4-ethoxyphenyl)ethanone (Compound 19 ) Step 16a: 1-(2-Iodo-4-methoxyphenyl)ethanone (Compound 0104-19)

[0167] Anhydrous AlCl3 (1.284g, 9.6mmol) was added to the mixture of 0103 (1.0g, 4.28mmol) and CS2 (4ml). The resulting mixture was heated to reflux (56°C) and then Ac 2 O (0.35 g, 3.42 mmol) was slowly added into the mixture. The mixture was refluxed for 1.5 hours and then CS2 was removed under reduced pressure. The dark residue was poured into ice-concentrated HCl, and extracted with ether three times. The extract was washed with H2O (100 ml x 2), 10% NaOH (100 ml x 2), and washed again with water until the water layer was colored. The organic layer was then washed with brine, dried over anhydrous NaSO4 and evaporated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum=1:5) to give the title compound 0104-19 as a pale red oil (160 mg, 14%): 1H NMR (CDCl 3 ) δ 2.60 (s, 3H), 3.83 (s, 3H), 6.92 (dd, 1H, J1 = 2.4 Hz, J2 = 8.7 Hz), 7.51 (d, 1H, J = 2.4 Hz), 7.58 (d, 1H, J = 8.7 Hz).

Step 16b: 1-(2-(4-Amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)-4-methoxyphenyl)ethanone (Compound 19)

[0168] Title compound 19 was prepared as a yellow solid (78mg, 31.7%) from compound 0113 (150mg, 0.646mmol), compound 0104-19 (160mg, 0.579mmol), neocuproine hydrate (15 mm, 0.0715 mmol), CuI (14mg, 0.0715 mmol) and NaOt-Bu (69 mg, 0.715 mmol), in anhydrous DMF (6 mL) using a procedure similar to that described for compound 17 (Example 14): LCMS: 381 [M+1]+; 1H NMR (DMSO-d6) δ 1.75 (m, 2H), 2.12 (m, 2H), 2.619 (s 3H), 2.77 (t, 1H, J = 2.4 Hz), 3.63 (s, 3H), 4.18 (t , 2H, J = 7.2 Hz), 5.92 (d, 1H, J = 2.1 Hz), 6.49 (s, 2H), 6.85 (d 1H, J = 6.0 Hz), 6.93 (dd, 1H, J1 = 2.4 Hz, J2 = 8.4 Hz), 7.75 (d, 1H, J = 6.0 Hz), 8.13 (d, 1H, J = 8.4 Hz).

Example 17: Preparation of 2-(5-fluoro-2-iodophenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 20) Step 17a: 2-(5-Fluoro-2-iodophenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205-20)

[0169] A mixture of compound 0204 (286 mg, 1.01 mmol), 4-fluoro-1,2-diidobenzene (447 mg, 1.2 mmol), NaOt-Bu (96 mg, 1 mmol), hydrate of neocurproin (21 mg, 0.1 mmol), and CuI (19 mg, 0.1 mmol), in dry DMF (9 mL) was stirred at 110°C overnight. The mixture was concentrated and purified by silica gel column chromatography (CH 2 Cl 2 /MeOH =100/1) to give the title compound 0205-20 as a white solid (260 mg, 51%): LCMS: 507 [M+1 ]+; * 1H NMR (DMSO-d6): δ 3.68 (s, 3H), 5.40 (s, 2H), 6.32 (dd, 1H, J1 = 2.7 Hz, J2 = 9.9 Hz), 6.56 (s, 2H ), 6.75 (d, 2 H, J = 8.7 Hz), 6.85 (m, 1 H), 6.90 (d, 1 H, J = 5.7 Hz), 7.07 (d, 2 H, J = 8.7 Hz), 7.76 (d, 1H, J = 5.7 Hz), 7.85 (m, 2H).

Step 17b: 2-(5-Fluoro-2-iodophenylthio)-1H-imidazo[4,5-c]pyridin-4-amine (compound 0206-20)

[0170] A mixture of compound 0205-20 (330 mg, 0.65 mmol), trifluoroacetic acid (3 mL) was stirred at reflux for 2 hours. The solvent was removed and the residue suspended in saturated aqueous NaHCO3 solution. The resulting solid was collected and dried to give the title compound 0206-20 as a white solid (250 mg, 98%):

[0171] LCMS: 387 [M+1]+; 1H NMR (DMSO-d6): δ 6.91 (d, 2 H, J = 6.3 Hz), 6.96 (m, 1 H), 7.09 (dd, 1 H, J1 = 3 Hz, J2 = 8.4 Hz), 7.56 ( d, 1H, J = 6.9 Hz), 7.85 (s, 2H), 7.92 (m, 1H).

Example 17c: 2-(5-Fluoro-2-iodophenylthio)-1-(pent-4-ynyl)-1H-c]pyridin-4-amine (Compound 20)

[0172] A mixture of compound 0206-20 (100mg, 0.26mmol), CS2CO3 (169mg, 0.52mmol), 5-chloropent-1-yne (40mg, 0.39mmol) and anhydrous DMF (5 ml) was stirred for 24 hours at 80°C. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH2Cl2/MeOH=20/1) to give the crude product as a pale white solid which was further purified by prep-HPLC to give the title compound 20 as a white solid (15 mg, 13%): LCMS: 453 [M+1]+; 1H NMR (DMSO-d6): δ 2.04 (m, 2 H), 2.18 (t, 2 H, J = 7.2 Hz), 2.80 (s, 1 H), 4.26 (t, 2 H, J = 7.5 Hz) , 6.48 (s, 2H), 6.61 (dd, 1H, J1 = 3 Hz, J2 = 9.6 Hz), 6.86 (d, 1H, J = 6 Hz), 6.94 (m, 1H), 7.76 (d, 1H, J = 6 Hz), 7.93(s, 2H).

Example 18: Preparation of 2-(4,5-Difluoro-2-iodophenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 21) Step 18a: 2-(4,5-Difluoro-2-iodophenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205-21)

[0173] Title compound 0205-21 was prepared (130mg, 14%) from compound 0204 (500mg, 1.75mmol 0, 1,2-difluoro-4,5-diidobenzene 91277mg, 3.49 mmol), NaOt-Bu (251 mg, 2.62 mmol), neocruproin hydrate (36 mg, 0.175 mmol), and CuI (33 mg, 0.175 mmol) in dry DMF (12 mL) using a procedure similar to that described for compound 0205-20 (Example 17): LCMS: 525 [M+1]+.

Step 18b: 2-(4,5-Difluoro-2-iodophenylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-21)

[0174] Title compound 0206-21 was prepared (140mg, 76%) from compound 0205-21 (240mg, 0.46mmol) and CF3COOH (4mL) using a procedure similar to that described for compound 0206 -20 (Example 17): LCMS: 405 [M+1]+.

Step 18c: 2-(4,5-Difluoro-2-iodophenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 21)

[0175] Title compound 21 was prepared (25mg, 18%) from compound 0206-21 9120mg, 0.30mmol), 5-chloropent-1-yne (46mg, 0.45mmol), CS2CO3 (164 mg, 0.50 mmol) and KI (5 mg) in DMF (5 mL) using a procedure similar to that described for compound 20 (Example 17): m.p: 105-110 °C. LCMS: 471 [M+1]+. 1H NMR: (DMSO-d6) δ 1.83 (m, 2H), 2.19 (m, 2H), 2.83 (t, J = 2.7 Hz, 1H), 4.25 (t, J = 7.2 Hz, 2H), 6.43 (s , 2H), 6.84 (d, J = 5.7 Hz, 1H), 7.05 (m, 1H), 7.73 (d, J = 6.0 Hz, 1H), 8.06 (m, 1H).

Example 19: Preparation of 2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(but-3-ynyl)-1H-imidazo[4,5-c]pyridin-4- amine (Compound 22) Step 19a: 2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205 -22)

[0176] Title compound 0205-22 was prepared as a brown solid (584 mg, 49%) from compound 0204 (700 mg, 2.44 mmol), 5-bromo-6-iodobenzo[d][1, 3]dioxol 91.20 g, 3.66mmol), neocuproin hydrate (51mg, 0.244mmol), CuI (46mg, 0.244mmol 0 and NaOt-Bu (234mg, 2.44mmol) in anhydrous DMF (31mL ) using a procedure similar to that described for compound 0205-20 (Example 17): LCMS: 485 [M+1]+; 1H NMR (DMSO-d6) δ 3.69 (s, 3H), 5.35 (s, 2H), 6.04 (s, 2H), 6.54 (s, 1H), 6.81 (m, 4H), 7.06 (d, 2H, J = 8.7 Hz), 7.29 (s, 1H).

Step 19b: 2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-22)

[0177] The title compound 0206-22 was prepared as a yellow solid (308 mg, 74%) from compound 0205-22 (557 mg, 1.15 mmol) and TFA (4 mL) using a procedure similar to that described for compound 0206-20 (Example 17): LCMS: 365 [M+1]+; 1H NMR (DMSO-d6) δ 6.07 (s, 2H), 6.58 (s, 2H), 6.69 (d, 1H, J = 6.0 Hz), 6.98 (s, 1H), 7.34 (s, 1H), 7.47 ( d, 1H, J = 6.0 Hz).

Step 19c: 2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(but-3-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine ( Compound 22)

[0178] A solution of 0206-22 (200 mg, 0.548 mmol), PPh3 (287 mg, 1.10 mmol), but-3-yn-1-ol (50 mg, 0.712 mmol), DIAD (332 mg, 1.644 mmol) in toluene (4 mL) and CH2Cl2 (1 mL) was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (CH2Cl2/MeOH in 30/1) and followed by pre-HPLC to give the title product 22 as a white solid (82mg, 36 %): m. P. 154 ~ 158 oC. LCMS: 417 [M+1]+; 1H NMR (DMSO-d6) δ 2.64 (m, 2H), 2.86 (m, 1H), 4.38 (t, 2H, J = 6.3 Hz), 6.07 (s, 2H), 6.40 (s, 2H), 6.66 ( s, 1H), 6.87 (d, 1H, J = 5.7 Hz), 7.35 (s, 1H), 7.71 (d, 1H, J = 5.4 Hz).

[0179] Example 20: Preparation of 1-(but-3-ynyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin -4- amine (Compound 23)

[0180] Title compound 23 was prepared as a white solid (134mg, 39.6%) from compound 0206-3 (300mg, 0.727mmol), PPh3 (381mg, 1.46mmol), but- 3-in-1-ol (66mg, 0.946mmol), DIAD (441mg, 2.18mmol) in toluene (6mL) and CH2Cl2 (1.5mL) using a procedure similar to that described for compound 22 (Example 19): m. P. 201 ~ 204 oC. LCMS: 465 [M+1]+; 1H NMR (DMSO-d6) δ 2.73 (m, 2H), 2.92 (t, 1H, J = 2.7 Hz), 4.50 (t, 2H, J = 6.6 Hz), 6.10 (s, 2H), 6.97 (s, 1H), 7.37 (d, 1H, J = 6.6 Hz), 7.52 (s, 1H), 7.76 (d, 1H, J = 9.0 Hz), 8.58 (d, 2H, J = 8.7 Hz), 13.29 (s, 1H).

Example 21: Preparation of 2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(hex-5-ynyl)-1H-imidazo[4,5-c]pyridin-4- amine (Compound 24)

[0181] Title compound 24 was prepared as a white solid (67mg, 27%) from compound 0206-22 (200mg, 0.548mmol), PPh3 (287mg, 1.10mmol), hex-5- in-1-ol (70mg, 0.712mmol), DIAD (332mg, 1.643mmol) in toluene (5mL) and CH2Cl2 (1.5mL) using a procedure similar to that described for compound 22 (Example 19): LCMS : 445 [M+1]+; 1H NMR (DMSO-d6) δ 1.44 (m, 2H), 1.78 (m, 2H), 2.17 (m, 2H), 2.77 (t, 1H, J = 2.7 Hz), 4.32 (t, 2H, J = 6.9 Hz), 6.13 (s, 2H), 7.02 (s, 1H), 7.30 (d, 1H, J = 6.6 Hz), 7.42 (s, 1H), 7.75 (d, 1H, J = 6.6 Hz), 8.54 ( s, 2H), 13.26 (s, 1H).

Example 22: Preparation of 1-(hex-5-ynyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4- amine (Compound 25)

[0182] Title compound 25 was prepared as a white solid (90mg, 25%) from compound 0206-3 (300mg, 0.727mmol), PPh3 (381mg, 1.46mmol), hex-5- in-1-ol (93 mg, 0.946 mmol), DIAD (441 mg, 2.18 mmol) in toluene (6 mL) and CH2Cl2 (1.5mL) using a procedure similar to that described for compound 22 (Example 19) :m. P. 158 ~ 162 oC. LCMS: 493 [M+1]+; 1H NMR (DMSO-d6) δ 1.45 (m, 2H), 1.77 (m, 2H), 2.18 (m, 2H), 2.77 (t, 1H, J = 2.7 Hz), 4.31 (t, 2H, J = 7.2 Hz), 6.10 (s, 2H), 7.00 (s, 1H), 7.31 (d, 1H, J = 7.5 Hz), 7.54 (s, 1H), 7.75 (d, 1H, J = 7.2 Hz), 8.56 ( d, 2H, J = 8.7 Hz), 13.25 (s, 1H).

Example 23: Preparation of 4-(4-amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanenitrile (Compound 26) Step 23a: 2-(2-Iodo-5-methoxyphenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205-26)

[0183] Title compound 0205-26 was prepared as a brown solid (734 mg, 55%) from compound 0204 (1g, 3.5 mmol), 1,2-diiodo-3-methoxybenzene (1.5 g, 4.2 mmol), neocuproin hydrate (73 mg, 0.35 mmol), CuI (66 mg, 0.35 mmol) and NaOt-Bu (335 mg, 3.5 mmol), in anhydrous DMF (33 mL) using a procedure similar to that described for compound 0205-20 (Example 17): LCMS: 519[M+1]+.

Step 23b: 2-(2-Iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-26)

[0184] The title compound 0206-26 was prepared as a yellow solid (181 mg, 53%) from compound 0205-26 (443 mg, 0.85 mmol) and TFA (4 mL using a procedure similar to that described for compound 0206-20 (Example 17): LCMS: 399 [M+1]+; 1H NMR (DMSO-d6) δ 3.61 (s, 3H), 6.72 (m, 5H), 7.51 (d, 1H, J = 6.3 Hz), 7.74 (d, 1H, J = 8.7 Hz).

Step 23c: 4-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanenitrile (Compound 26)

[0185] A mixture of compound 0206-26 (150 mg, 0.38 mmol), 4-bromobutanenitrile (83.6 mg, 0.565 mmol), CS2CO3 (208 mg, 0.64 mmol) in DMF (5 mL) was stirred at 80°C for 2 hours. The mixture was evaporated to remove DMF and purified first by silica gel column chromatography (100/1 CH2Cl/MeOH) and then by pre-HPLC to give the title compound 26 as a white solid (20 mg, 11 .3%): m. p.146 ~ 150 oC. LCMS: 466 [M+1]+; 1H NMR (DMSO-d6) δ 1.95(m, 2H), 2.54 (m, 2H), 3.59 (s, 3H), 4.24 (t, 2H, J = 7.5 Hz), 6.31 (d, 1H, J = 3.3 Hz), 6.48 (s, 2H), 6.69 (dd, 1H, J1 = 2.7 Hz, J2 = 8.7 Hz), 6.85 (d, 1H, J = 6.0 Hz), 7.77 (m, 2H).

Example 24: Preparation of 4-(4-amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanenitrile (Compound 27)

[0186] Title compound 27 was prepared as a light yellow solid (43 mg, 24%) from compound 02060-22 (150 mg, 0.411 mmol), 4-bromobutanenitrile (91 mg, 0.616 mmol), Cs2CO3 (227 mg, 0.699 mmol) in DMF (6 mL) using a procedure similar to that described for compound 26 (Example 23): m. P. 140 ~ 149 oC. LCMS: 432 [M+1]+; 1H NMR (DMSO-d6) δ 1.96 (m, 2H), 2.56 (t, 2H, J = 7.2 Hz), 4.25 (t, 2H, J = 7.8 Hz), 6.08 (s, 2H), 6.39 (s, 2H), 6.70 (s, 1H), 6.83 (d, 1H, J = 8.4 Hz), 7.36 (s, 1H), 7.73 (d, 1H, J = 5.7 Hz).

Example 25: Preparation of 4-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanenitrile (Compound 28)

[0187] Title compound 28 was prepared as a white solid (82mg, 39%) from compound 0206-3 (180mg, 0.437mmol), 4-bromobutanenitrile (97mg, 0.655mmol), Cs2CO3 (241mg , 0.743 mmol) in DMF (6.3 mL) using a procedure similar to that described for compound 26 (Example 23): m. P. 210 ~ 222 oC. LCMS: 480 [M+1]+; 1H NMR (DMSO-d6) δ 2.05 (m, 2H), 2.62 (t, 2H, J = 7.2 Hz), 4.36 (t, 2H, J = 7.2 Hz), 6.10 (s, 2H), 7.00 (s, 1H), 7.30 (d, 1H, J = 7.5 Hz), 7.53 (s, 1H), 7.77 (d, 1H, J = 6.9 Hz), 8.52 (s, 2H), 13.07 (s, 1H).

Example 26: Preparation of 5-(4-amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanenitrile (Compound 29)

[0188] Title compound 29 was prepared as a pale yellow solid (68mg, 37%) from compound 0206-22 (150mg, 0.411mmol), 5-bromopentanenitrile (100mg, 0.616mmol), Cs2CO3 (227mg , 0.699 mmol) in DMF (6 mL) using a procedure similar to that described for compound 26 (Example 23): m. P. 133 ~ 135 oC. LCMS: 446 [M+1]+; 1H NMR (DMSO-d6) δ 1.51 (m, 2H), 1.73 (m, 2H), 2.50 (m, 2H), 4.21 (t, 2H, J = 6.6 Hz), 6.07 (s, 2H), 6.38 ( s, 2H), 6.69 (s, 1H), 6.84 (d, 1H, J = 7.5 Hz), 7.36 (s, 1H), 7.72 (d, 1H, J = 6.0 Hz).

Example 27: Preparation of 5-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanenitrile (Compound 30)

[0189] Title compound 30 was prepared as a white solid (92mg, 48%) from compound 0206-3 (162mg, 0.393mmol), 5-bromopentanenitrile (96mg, 0.590mmol), Cs2CO3 (217mg , 0.668 mmol) in DMF (5.7 mL) using a procedure similar to that described for compound 26 (Example 23): m. P. 179 ~ 191 oC. LCMS: 494 [M+1]+; 1H NMR (DMSO-d6) δ 1.58 (m, 2H), 1.80 (m, 2H), 2.53 (m, 2H), 4.33 (t, 2H, J = 6.6 Hz), 6.10 (s, 2H), 7.02 ( s, 1H), 7.33 (d, 1H, J = 7.5 Hz), 7.54 (s, 1H), 7.77 (d, 1H, J = 7.2 Hz), 8.55 (s, 2H), 13.21 (s, 1H).

Example 28: Preparation of 1-(2-aminoethyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine ( Compound 32) Step 28a: 2-(2-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl) ethyl)isoindoline-1,3-dione (Compound 0302-32)

[0190] A mixture of compound 0206-3 (500mg, 1.2mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (457mg, 1.8mmol), and Cs2CO3 (672mg, 2.1 mmol) in anhydrous DMF (8 mL) was stirred at 50°C for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated under high vacuum to give the crude product as an orange solid which was purified by silica gel column chromatography (CH2Cl2/MeOH=100/1) to provide the title compound 0302-32 as a pale yellow solid ( 390 mg, 56%): LC-MS: 586 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 3.92 (t, 2H, J = 5.3 Hz), 4.50 (t, 2H, J = 5.3 Hz), 6.00 (s, 2H), 6.38 (s, 2H), 6.49 (s, 1H), 6.75 (d, 1H, J = 6.0 Hz), 7.19 (s, 1H), 7.64 (d, 1H, J = 6.0 Hz), 7.73 (m, 4H).

Step 28b: 1-(2-Aminoethyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 32 )

[0191] A mixture of compound 0302-32 (5 g, 8.55 mmol) and N2H4-H2O (4.28 g, 85.5 mmol) in CH2Cl2 (150 mL) and EtOH (15 mL) was stirred at 50°C for 2 hours. The solid was filtered off and the filtrate was washed with brine 9100 mL x 2), dried over Na 2 SO 4 , filtered and evaporated to give the title compound 32 as a white solid (3 g, 77%): m. P. 111 ~121 oC. LC-MS: 456 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 1.46 (s, 2H) 2.80 (t, 2H, J = 6.3 Hz), 4.16 (t, 2H, J = 6.6 Hz), 6.05 (s, 2H), 6.29 ( s, 2H), 6.69 (s, 1H), 6.84 (d, 1H, J = 6.0 Hz), 7.46 (s, 1H), 7.70 (d, 1H, J = 5.7 Hz).

Example 29: Preparation of 2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 33) Step 29a: 2-(2-(4-Amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl) ethyl)isoindoline-1,3-dione (Compound 0302-33)

[0192] Title compound 0302-33 was prepared as a pale yellow solid (720 mg, 50%) from compound 0206-22 (975 mg, 2.67 mmol), 2-(2-bromoethyl)isoindoline- 1,3-dione (1.017 g, 4.00 mmol), CS2CO3 (1.475 g, 4.54 mmol) in anhydrous DMF (38 mL) using a procedure similar to that described for compound 0302-32 (Example 28): LCMS : 538 [M+1]+.

Step 29b: 1-(2-Aminoethyl)-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0303 -33)

[0193] The title compound 0303-33 was prepared as a pale yellow solid (495 mg, 91%) from compound 0302-33 (720 mg, 1.337 mmol) and N2H4-H2O (886 mg, 14.71 mmol ) in CH2Cl2 (27 mL) and EtOH (3 mL) using a procedure similar to that described for compound 0303-32 (Example 28): LCMS:408 [M+1]+.

Step 2 9c: 2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4- amine (Compound 33)

[0194] To a solution of compound 0303-33 (150 mg, 0.613 mmol) in methanol (10 mL) was added pivalaldehyde (63 mg, 0.736 mmol). Then the mixture was stirred for 30 minutes at room temperature, NaBH 3 CN (154 mg, 2.452 mmol) was slowly added, and the mixture was stirred for an additional 30 minutes. The reaction was quenched by addition of saturated NaHCO 3 910 mL) and the resulting mixture was diluted with water (9100 mL) and extracted with dichloromethane (50 x 2). The combined organic layer was concentrated to separate a residue which was purified by pre-HPLC to give the title compound 33 as a white solid (60 mg, 20%): m.p. 181 ~ 187 oC. LCMS: 478 [M+1]+; 1H NMR (DMSO-d6) δ 0.76 (s, 9H), 1.61 (s, 1H), 2.18 (s, 2H), 2.76 (t, 2H, J = 6.3 Hz), 4.24 (t, 2H, J = 6.3 Hz), 6.06 (s, 2H), 6.31 (s, 2H), 6.62 (s, 1H), 6.83 (d, 1H, J = 5.7 Hz), 7.34 (s, 1H), 7.70 (d, 1H, J = 5.7 Hz).

Example 30: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 34)

[0195] Title compound 34 was prepared as a white solid (2.718 g, 26%) from compound 32 (9.1 g, 19.9 mmol), pivalaldehyde (2.06 g, 24 mmol) and NaBH3CN (5.027 g, 80 mmol) using a procedure similar to that described for compound 33 (Example 29): m.p. 203 ~ 207 oC. LCMS: 526 [M+1]+; 1H NMR (DMSO-d6) δ 0.77 (s, 9H), 1.60 (s, 1H), 2.18 (s, 2H), 2.75 (t, 2H, J = 5.7 Hz), 4.23 (t, 2H, J = 5.4 Hz), 6.04 (s, 2H), 6.33 (s, 2H), 6.58 (s, 1H), 6.83 (d, 1H, J = 6.0 Hz), 7.46 (s, 1H), 7.77 (d, 1H, J = 5.7 Hz).

Example 30(Method 2): Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c ]pyridin-4-amine (Compound 34) Step 30a': 2-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethylacetate ( Compound 0402-34)

[0196] A mixture of compound 0206-3 (300 mg, 0.728 mmol), 2-bromoethyl acetate (182 mg, 1.092 mmol) and CS2CO3 (402 mg, 1.24 mmol) in DMF (10 mL) was stirred at 85°C for 2 hours. DMF was evaporated in vacuo and the residue was purified by silica gel column chromatography (100:1 methylene chloride/methanol) to give the title compound 0402-34 as a white solid (188 mg, 50.4%): LCMS : 499 [M+1]+; 1H NMR (DMSO-d6) δ 1.86 (s, 3H), 4.26 (t, 2H, J = 4.8 Hz), 4.45 (t, 2H, J = 4.8 Hz), 6.03 (s, 2H), 6.35 (s, 2H), 6.68 (s, 1H), 6.81 (d, 1H, J = 6.0 Hz), 7.76 (s, 1H), 7.71 (d, 1H, J = 6.0 Hz).

Step 30b': 2-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethanol ( Compound 0403-34)

[0197] A suspension of compound 0402-34 (180 mg, 0.36 mmol) in MeOH (3 mL) was treated with K2CO3 (60 mg, 0.43 mmol) at 50°C for 1 hour. The mixture was diluted with water (15 mL) and filtered to provide the title compound 0403-34 as a white solid (150 mg, 91%): LCMS: 457 [M+1]+; 1H NMR (DMSO-d6) δ 3.63 (m, 2H), 4.27 (t, 2H, J = 5.4 Hz), 4.98 (t, 2H, J = 5.7 Hz), 6.05 (s, 2H), 6.31 (s, 2H), 6.69 (s, 1H), 6.80 (d, 1H, J = 6.0 Hz), 7.46 (s, 1H), 7.69 (d, 1H, J = 5.7 Hz).

Step 30c': 2-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethyl methanesulfonate (Compound 0404-34)

[0198] Compound 0403-34 (133 mg, 0.292 mmol) was dissolved in hot anhydrous dioxane (4 mL). The solution was cooled to 40°C and then treated with Net3 (89 mg, 0.876 mmol) and MsCl (50 mg, 0.438 mmol) for 20 minutes. The mixture was concentrated and purified by silica gel column chromatography (CH 2 Cl 2 /MeOH = 50/1) to provide the title compound 0404-34 as a white solid (122 g, 78.3%): LCMS: 535 [M +1]+; 1H NMR (DMSO-d6) δ 3.07 (s, 3H), 4.46 (t, 2H, J = 4.5 Hz), 4.59 (t, 2H, J = 5.1 Hz), 6.05 (s, 2H), 6.59 (s, 2H), 6.71 (s, 1H), 6.90 (d, 1H, J = 6.0 Hz), 7.48 (s, 1H), 7.73 (d, 1H, J = 6.6 Hz).

Step 30d': 2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4- amine (Compound 34)

[0199] A mixture of compound 0404-34 9170 mg, 0.318 mmol) 2,2-dimethylpropan-1-amine hydrochloride (786 mg, 6.36 mmol) and K2CO3 (1.318 g, 9.54 mmol) in toluene ( 10 ml) was heated at 60°C for 1 hour. The solvent was removed and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH = 40/1) and then pre-HPLC to provide the title compound 34 as a pale yellow solid (25 mg, 15% ): m.p. 193 ~ 201 oC. LCMS: 526 [M+1]+; 1H NMR (DMSO-d6) δ 0.77 (s, 9H), 1.60 (s, 1H), 2.18 (s, 2H), 2.75 (t, 2H, J = 5.7 Hz), 4.23 (t, 2H, J = 5.4 Hz), 6.04 (s, 2H), 6.33 (s, 2H), 6.58 (s, 1H), 6.83 (d, 1H, J = 6.0 Hz), 7.46 (s, 1H), 7.77(d, 1H, J = 5.7 Hz).

Example 31: Preparation of 2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4.5 -c]pyridin-4-amine (Compound 37) Step 31a: 2-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin- 4-amine (Compound 0205-37)

[0200] Title compound 0205-37 was prepared as a brown solid (2.2 g, 38%) from compound 0204 (3 g, 10.5 mmol), 6,7-diiodo-2,3- dihydrobenzo[b][1,4]dioxin (01077) (8.1 g, 21 mmol), neocuproine hydrate (0.2 g, 1.05 mmol), CuI (0.2 g, 1.05 mmol) and NaOt-Bu (1.5 g, 15.7 mmol) in anhydrous DMF (100 mL) using a procedure similar to that described for compound 0205-20 (Example 17): LCMS: 547[M+1]+; 1H NMR (DMSO-d6) δ 3.69 (s, 3H), 4.19 (m, 4H), 5.49 (s, 2H), 6.68 (s, 1H), 6.83 (d, 2H, J = 8.4 Hz), 7.11 ( d, 2H, J = 8.7 Hz), 7.28 (d, 1H, J = 7.2 Hz), 7.35 (s, 1H), 7.71 (d, 1H, J = 7.2 Hz), 8.42 (s, 2H), 13.36 ( s, 1H).

Step 31b: 2-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-37 )

[0201] Title compound 0206-37 was prepared as a yellow solid (1.5 g, 88%) from compound 0205-37 (2.2 g, 4 mmol) was dissolved in TFA (210 mL) using a procedure similar to that described for compound 0206-20 (Example 17): LCMS: 427 [M+1]+; 1H NMR (DMSO-d6) δ 4.29 (m, 4H), 6.96 (d, 1H, J = 6.9 Hz), 7.20 (s, 1H), 7.50 (s, 1H), 7.63 (d, 1H, J = 6.9 Hz), 8.42 (s, 2H), 13.36 (s, 1H).

Step 31c: 2-(2-(4-Amino-2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1H-imidazo[4,5-c] pyridin-1-yl)ethyl)isoindoline-1,3-dione(Compound 0302-37)

[0202] Title compound 0302-37 was prepared as a white solid (1.2 g, 57%) from compound 0206-37 (1.5 g, 3.5 mmol), 2-(2-bromoethyl )isoindoline-1,3-dione (1.34 g, 5.3 mmol), CS2CO3 (1.94 g, 6.0 mmol) and DMF (50 mL) using a procedure similar to that described for compound 0302-32 (Example 28): LCMS: 600 [M+1]+; 1H NMR (DMSO-d6) δ 3.92 (t, 2H, J = 5.7 Hz), 4.16 (m , 4H), 4.48 (t, 2H, J = 4.8 Hz), 6.38 (s, 2H), 6.41 (s, 1H), 6.75 (d, 1H, J= 6 Hz), 7.15 (s, 1H), 7.64 (d, 1H, J= 5.7 Hz), 7.77 (m, 4H).

Step 31d: 1-(2-Aminoethyl)-2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1H-imidazo[4,5-c]pyridin- 4-amine (Compound 0303-37)

[0203] Title compound 0303-37 was prepared as a pale yellow solid (790 mg, 84%) from compound 0302-37 (1.2 g, 2 mmol) and N2H4-H2O (1 g, 20 mmol ) in CH2Cl2 (28 mL) and EtOH (3 mL) using a procedure similar to that described for compound 0303-32 (Example 28): LC-MS: 470 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 2H), 2.77 (t, 2H, J = 6.6 Hz), 4.16 (m, 6H), 6.27 (s, 2H), 6.53 (s, 1H) , 6.81 (d, 1H, J = 6 Hz), 7.35 (s, 1H), 7.67 (d, 1H, J = 5.7 Hz).

Step 31e: 2-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c ] pyridin-4-amine (Compound 37)

[0204] The title compound 37 was prepared as a white solid (128mg, 14%) from compound 0303-37 (790mg, 1.7mmol), pivalaldehyde (217mg, 2.5mmol) and NaBH3CN (423 mg, 6.7 mmol) using a procedure similar to that described for compound 33 (Example 29): m.p. 193~200 oC. LCMS: 540 [M+1]+; 1H NMR (DMSO-d6) δ 0.793 (s, 9H), 2.32 (s, 2H), 2.88 (t, 2H, J = 6.3 Hz), 4.18 (m, 4H), 4.32 (t, 2H, J= 6.6 Hz), 6.50 (s, 1H), 6.76 (s, 2H), 6.94 (d, 1H, J = 6Hz), 7.37 (s, 1H), 7.73 (d, 1H, J = 6.3 Hz).

Example 32: Preparation of 1-(2-(tert-butylamino)ethyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin -4- amine (Compound 40)

[0205] A solution of compound 0404-34 (250 mg, 0.47 mmol) in tert-butylamino (30 mL) was stirred at 60°C for 24 hours in a pressure vessel. The solvent was removed and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH = 50/1) and followed by pre-HPLC to provide the title compound 40 as a white solid (34 mg, 15%) : m.p. 194 ~ 197 oC. LCMS: 512 [M+1]+; 1H NMR (DMSO-d6) δ 0.88 (s, 9H), 1.60 (s, 1H), 2.70 (t, J = 6.0 Hz, 2H), 4.20 (t, J = 6.0 Hz, 2H), 6.05 (s , 2H), 6.35 (s, 2H), 6.70 (s, 1H), 6.83 (d, J = 6.0 Hz, 1H), 7.48 (s, 1H), 7.72(d, J = 6.0 Hz, 1H).

Example 33: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(isopropylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 42)

[0206] The title compound 42 was prepared as a white solid (40 mg, 17%) from compound 0404-34 (252 mg, 0.47 mmol) in isopropylamine (30 mL) using a procedure similar to that described for compound 40 (Example 32): m.p. 170 ~ 172oC. LCMS: 498 [M+1]+; 1H NMR (DMSO-d6) δ 0.86 (d, J = 6.3 Hz, 6 H), 1.68 (s, 1H), 2.62 (m, 1H), 2.74 (t, J = 6.6 Hz, 2H), 4.21 (t , J = 6.6 Hz, 2H), 6.04 (s, 2H), 6.36 (s, 2H), 6.67 (s, 1H), 6.82 (d, J = 6.0 Hz, 1H), 7.47 (s, 1H), 7.71 (d, J = 6.0 Hz, 1H).

Example 34: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(pentan-3-ylamino)ethyl)-1H-imidazo[4,5-c ] pyridin-4-amine (Compound 44)

[0207] To a solution of compound 32 (228 mg, 0.5 mmol) in methanol (9 mL) was added 3-pentanone (65 mg, 0.75 mmol). After the reaction was stirred for 30 minutes at room temperature, NaBH3CN (125 mg, 2 mmol) was slowly added. Traces of CH3COOH were added and the mixture was stirred overnight. The reaction was quenched by addition of saturated NaHCO3 (20 mL). The mixture was diluted with water (100 ml) and extracted with dichloromethane (50 ml x 3). The extract was concentrated and purified by pre-HPLC to give the title compound 44 as a white solid (139 mg, 53%): m.p. 142 ~ 147 oC. LCMS: 526 [M+1]+; 1H NMR (DMSO-d6): δ 0.75 (t, J = 6.6 Hz, 6 H), 1.31 (m, 4 H), 2.42 (m, 1 H), 2.85 (t, J = 7.2 Hz, 2 H) , 4.33 (t, J = 7.2 Hz, 2 H), 6.06 (s, 2 H), 6.52 (s, 2 H), 6.66 (s, 1 H), 6.92 (d, J = 6.3 Hz, 1 H) , 7.49 (s, 1H), 7.74 (d, J = 6.0 Hz, 1H).

Example 35: Preparation of 1-(2-(dimethylamino)ethyl)-2-(6-

[0208] Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 46)

[0209] To a solution of compound 32 9150 mg, 0.32 mmol) in methanol (6 mL) was added to an aqueous HCHO solution (52 mg, 0.64 mmol). After stirring for 30 minutes at room temperature, NaBH3CN (81 mg, 1.28 mmol) was slowly added, and the mixture was stirred overnight. The reaction was terminated by addition of saturated NaHCO3 (10 ml). The mixture was diluted with water (100 ml) and extracted with dichloromethane (50 ml x 2). The extract was concentrated and purified by pre-HPLC to give the title compound 46 (30 mg, 19%) as a white solid. m.p. 170 ~ 172 oC; LCMS: 484[M+1]+; H NMR (DMSO-d6): δ 2.14 (s, 6 H), 2.48 (t, J = 6.3 Hz, 2 H), 4.27 (t, J = 6.3 Hz, 2 H), 6.05 (s, 2 H) , 6.38 (s, 2 H), 6.67 (s, 1 H), 6.81 (d, J = 6.0 Hz, 1 H), 7.48 (s, 1 H), 7.72(d, J = 6.0 Hz, 1 H) .

Example 36: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(methylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4 - amine (Compound 48)

[0210] The title compound 48 was prepared as a white solid (40 mg, 18%) from compound 0404-34 (250 mg, 0.47 mmol) in an alcoholic solution of methylamine (30 mL) using a procedure similar to that described for compound 40 (Example 32): m.p. 145 ~ 155°C. LCMS: 470 [M+1]+; 1 H NMR (DMSO-d6) δ 1.85 (s, 1 H), 2.23 (s, 6H), 2.73 (t, J = 6.6 Hz, 2H), 4.24 (t, J = 6.6 Hz, 2H), 6.05 ( s, 2H), 6.34 (s, 2H), 6.68 (s, 1H), 6.82 (d, J = 6.0 Hz, 1H), 7.47 (s, 1H), 7.71(d, J = 6.0 Hz, 1H).

Example 37: Preparation of 2-(2-iodo-5-methoxyphenylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 50) Step 37a: 2-(2-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethyl)isoindoline-1,3-dione (Compound 0302-50)

[0211] The title compound 0302-50 was prepared as a white solid (315 mg, 44%) from the compound 2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin -4-amine (Compound 0206-26) (500 mg, 1.256 mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (478 mg, 1.884 mmol) and CS2CO3 (694 mg, 2.135 mmol) in DMF anhydrous solution (18 mL) using a procedure similar to that described for compound 0302-32 (Example 28): LCMS: 572 [M+1]+.

Step 37b: 1-(2-Aminoethyl)-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0303-50)

[0212] The title compound 0303-50 was prepared as a white solid (206 mg, 86%) from compound 0302-50 (310 mg, 0.543 mmol), and N2H4-H2O (320 mg, 5.43 mmol ) in CH2Cl2 (10 mL) and EtOH (2 mL) using a procedure similar to that described for compound 0303-32 (Example 28): LCMS: 442 [M+1]+.

Step 37c: 2-(2-Iodo-5-methoxyphenylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 50)

[0213] The title compound 50 was prepared as a white solid (45mg, 28%) from compound 0303-50 (140mg, 0.317mmol), pivalaldehyde (33mg, 0.381mmol) and NaBH3CN (80mg, 1.268 mmol) using a procedure similar to that described for compound 33 (Example 29): m.p. 155 ~ 167oC. LCMS: 512 [M+1]+; 1H NMR (DMSO-d6) δ 0.76 (s, 9H), 2.15 (s, 2H), 2.74 (t, 2H, J = 6.3 Hz), 3.58 (s, 3H), 4.22 (t, 2H, J = 6.3 Hz), 6.30 (d, 1H, J = 2.4 Hz), 6.43 (s, 2H), 6.67 (dd, 1H, J1 = 3.0 Hz, J2 = 9.0 Hz), 6.85 (d, 1H, J = 6.07 Hz ), 7.74 (m, 2H).

Example 38: Preparation of 2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 51) Step 38a: Propyl 3-(4-Amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)acetate (Compound 0402-51)

[0214] A mixture of compound 0206-22 (500 mg, 1.37 mmol), bromopropyl 3-acetate (372 mg, 2.05 mmol) and CS2CO3 (757 mg, 2.33 mmol) in DMF (17 mL ) was stirred at 85°C for 2 hours. DMF was evaporated in vacuo and the residue was purified by silica gel column chromatography (100:1 methylene chloride/methanol) to give the title compound 0402-51 as a white solid (340 mg, 53%): LCMS : 465 [M+1]+; 1H NMR (DMSO-d6) δ 1.92 (m, 5H), 3.94 (t, 2H, J = 5.7 Hz), 4.27 (t, 2H, J = 6.9 Hz), 6.07 (s, 2H), 6.39 (s, 2H), 6.64 (s, 1H), 6.80 (d, 1H, J = 6.0 Hz), 7.36 (s, 1H), 7.72 (d, 1H, J = 5.7 Hz).

Step 38b: 3-(4-Amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propan-1 -ol (Compound 0403-51)

[0215] A suspension of compound 0402-51 (340 mg, 0.73 mmol) in MeOH (7 mL) was treated with K2CO3 (122 mg, 0.88 mmol) at 50°C for 1 hour. The mixture was diluted with water (24 mL) and filtered to provide the title compound 0403-51 as a white solid (264 mg, 85%): LCMS: 423 [M+1]+; 1H NMR (DMSO-d6) δ 1.78 (m, 2H), 3.39 (m, 2H), 4.24 (t, 2H, J = 7.2 Hz), 4.65 (t, 2H, J = 4.8 Hz), 6.08 (s, 2H), 6.35 (s, 2H), 6.67 (s, 1H), 6.80 (d, 1H, J = 5.7 Hz), 7.36 (s, 1H), 7.71 (d, 1H, J = 6.0 Hz).

Step 38c: 3-(4-Amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propyl methane- sulfonate (040451)

[0216] Compound 0403-51 (264 mg, 0.624 mmol) was diluted in hot anhydrous dioxane (8.6 mL). The solution was cooled to 40°C and treated with Net3 (189 mg, 1.87 mmol) and MsCl (107 mg, 0.935 mmol) for 20 minutes. The mixture was concentrated and purified by silica gel column chromatography (CH2Cl2/MeOH = 50/1) to give the title compound 0404-51 as a white solid (143 g, 50%): LCMS: 501 [M+1 ]+.

Step 38d: 2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 51)

[0217] A solution of compound 0404-51 (113 mg, 0.225 mmol) in isopropylamino (5 mL) was stirred at 60°C for 1 hour in a pressure vessel. The solvent was removed and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH = 40/1) to provide the title compound 51 as a white solid (31 mg, 30%): m.p. 140 ~ 149 oC. LCMS: 464 [M+1]+; 1H NMR (DMSO-d6) δ 1.05 (m, 6H), 1.91 (m, 2H), 2.67 (t, 2H, J = 7.2 Hz), 2.89 (m, 1H), 4.27 (t, 2H, J = 7.5 Hz), 6.08 (s, 2H), 6.38 (s, 2H), 6.68 (s, 1H), 6.88 (d, 1H, J = 5.7 Hz), 7.37 (s, 1H), 7.73 (d, 1H, J = 6.0 Hz).

Example 39: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-lithio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 52) Step 39a: Propyl 3-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)acetate (Compound 0402-52)

[0218] The title compound 0402-52 was prepared as a white solid (310 mg, 50%) from the compound 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H- imidazo[4,5-c]pyridin-4-amine (Compound 0206-3) (500 mg, 1.213 mmol), 3-bromopropyl acetate (329 mg, 1.819 mmol) and CS2CO3 (670 mg, 2.062 mmol) in DMF (17 mL) using a procedure similar to that described for compound 0402-51 (Example 38).

Step 39b: 3-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propan-1 -ol (Compound 0403-52)

[0219] Title compound 0403-52 was prepared as a white solid (250 mg, 88%) from compound 0402-52 (310 mg, 0.605 mmol) and K2CO3 (100 mg, 0.727 mmol) in MeOH (5 mL) using a procedure similar to that described for compound 0403-51 (Example 38):

[0220] LCMS: 471 [M+1]+; 1H NMR (DMSO-d6) δ 1.78 (m, 2H), 3.39 (m, 2H), 4.22 (t, 2H, J = 6.9 Hz), 4.64 (t, 2H, J = 4.8 Hz), 6.05 (s, 2H), 6.33 (s, 2H), 6.66 (s, 1H), 6.79 (d, 1H, J = 6.0 Hz), 7.48 (s, 1H), 7.71 (d, 1H, J = 5.7 Hz).

Step 39c: 3-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propyl methanesulfonate ( Compound 0404-52)

[0221] Title compound 0404-52 was prepared as a white solid (181 g, 62%) from compound 0403-52 (250 mg, 0.532 mmol), Net3 9161 mg, 1.596 mmol) and MSCl (91 mg , 0.798 mmol) using a procedure similar to that described for compound 0404-51 (Example 38): LCMS: 549 [M+1]+; 1H NMR (DMSO-d6) δ 2.08 (m, 2H), 3.16 (s, 3H), 4.25 (m, 4H), 6.05 (s, 2H), 6.39 (s, 2H), 6.67 (s, 1H), 6.82 (d, 1H, J = 5.7 Hz), 7.48 (s, 1H), 7.73 (d, 1H, J = 5.7 Hz).

Step 39d: 2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 52)

[0222] The title compound 52 was prepared as a white solid (54 mg, 32%) from compound 0404-52 (180 mg, 0.328 mmol) in isopropylamino (5 mL) using a procedure similar to that described for compound 51 (Example 38): m.p. 185 ~ 193 oC. LCMS: 512 [M+1]+; 1H NMR (DMSO-d6) δ 0.97 (m, 6H), 1.81 (m, 2H), 2.55 (m, 2H), 2.73 (m, 1H), 4.24 (t, 2H, J = 6.3 Hz), 6.05 (s, 2H), 6.38 (s, 2H), 6.65 (s, 1H), 6.84 (d, 1H, J = 5.4 Hz), 7.48 (s, 1H), 7.72(d, 1H, J = 5.7 Hz) .

Example 40: Preparation of 2-(2-bromo-5-methoxyphenylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 53) Step 40a: 2-(2-Bromo-5-methoxyphenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205-53)

[0223] A mixture of compound 0204 91.549 g, 5.41 mol), 1-bromo-2-iodo-4-methoxybenzene (Compound 0104-13) (2.54 g, 8.115 mol), neocuproine hydrate (113 mg , 0.541 mmol), CuI (103 mg, 0.541 mmol) and NaOt-Bu (519 mg, 5.41 mmol) in anhydrous DMF (50 mL) was stirred for 24 hours at 110 °C (oil bath) under an atmosphere of nitrogen. The solvent was removed under high vacuum and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH at 100/1) to give the title compound 0205-53 as a brown solid (1.67 g, 65%): LCMS: 471 [M+1]+.

Step 40b: 2-(2-Bromo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-53)

[0224] Compound 0205-53 (1.67 g, 3.55 mmol) was dissolved in TFA (12 mL) and stirred for 2 hours at 80°C. The solvent was evaporated and the residue was adjusted to pH 7 with saturated NaHCO 3 . The resulting precipitate was collected by filtration and further purified by silica gel column chromatography (30/1 CH 2 Cl 2 /MeOH) to give the title compound 0206-53 as a yellow solid (1,105 g, 88%): LCMS: 351 [M+1]+; 1H NMR (DMSO-d6) δ 3.65 (s, 3H), 6.78 (m, 3H), 7.08 (s, 2H), 7.55 (m, 2H).

Step 40c: Propyl 3-(4-Amino-2-(2-bromo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)acetate (Compound 040253)

[0225] The title compound 0402-53 was prepared as a light yellow solid (750 mg, 53%) from compound 020653 (1.105 g, 3.15 mmol), 3-bromopropyl acetate (855 mg, 4. 72 mmol) and CS2CO3 (1.74 g, 5.35 mmol) in DMF (57 mL) using a procedure similar to that described for compound 040251 (Example 38): LCMS: 451 [M+1]+.

Step 40d: 3-(4-Amino-2-(2-bromo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propan-1-ol (Compound 0403-53)

[0226] Title compound 0403-53 was prepared as a white solid (560 mg, 82%) from compound 0402-53 (750 mg, 1.66 mmol) and K2CO3 (276 mg, 1.99 mmol) in MeOH (13 mL) using a procedure similar to that described for compound 0403-51 (Example 38): LCMS: 409 [M+1]+; 1H NMR (DMSO-d6) δ 1.78 (m, 2H), 3.37 (m, 2H), 3.61 (s, 3H), 4.25 (t, 2H, J = 7.2 Hz), 4.63 (t, 1H, J = 5.4 Hz), 6.32 (d, 1H, J = 3.0 Hz), 6.44 (s, 2H), 6.83 (m, 2H), 7.60 (d, 1H, J = 9.0 Hz), 7.74 (d, 1H, J = 5.7 Hz).

Step 40e: 3-(4-Amino-2-(2-bromo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propyl methanesulfonate (Compound 0404-53)

[0227] Title compound 0404-52 was prepared as a white solid (300 g, 47%) from compound 0403-53 (560 mg, 1.368 mmol), Net3 (415 mg, 4.105 mmol) and MsCl (235 mg, 2.052 mmol) using a procedure similar to that described for compound 0404-51 (Example 38): LCMS: 487 [M+1]+.

Step 40f: 2-(2-Bromo-5-methoxyphenylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine (53)

[0228] The title compound 53 was prepared as a white solid (54 mg, 32%) from compound 0404-53 (300 mg, 0.639 mmol) in isopropylamine (20 mL) using a procedure similar to that described for the compound 51 (Example 38): m.p. 125 ~ 129 oC. LCMS: 450 [M+1]+; 1H NMR (DMSO-d6) δ 0.89 (d, 6H, J = 5.4 Hz), 1.51 (s, 1H), 1.74 (m, 2H), 2.38 (t, 2H, J = 6.9 Hz), 2.55 (m , 1H), 3.60 (s, 3H), 4.24 (t, 2H, J = 7.2 Hz), 6.33 (d, 1H, J = 2.4 Hz), 6.46 (s, 2H), 6.84 (m, 2H), 7.60 (d, 1H, J = 8.7 Hz), 7.72(d, 1H, J = 5.4 Hz).

Example 41: Preparation of 2-(2-iodo-5-methoxyphenylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 54) Step 41a: 2-(2-Iodo-5-methoxyphenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205-54)

[0229] Title compound 0205-54 was prepared as a brown solid (734 mg, 55%) from compound 0204 (1 g, 3.5 mmol), 1,2-diido-4-methoxybenzene (compound 0104 -12) (1.5g, 4.2mmol), neocuproin hydrate (73mg, 0.35mmol), CuI (66mg, 0.35mmol) and NaOt-Bu (335mg, 3.5mmol ) and anhydrous DMF using a procedure similar to that described for compound 0205-53 (Example 40): LCMS: 519[M+1]+.

Step 41b: 2-(2-Iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-54)

[0230] Title compound 0206-54 was prepared as a yellow solid (181 mg, 53%) from compound 0205-54 (443 mg, 0.85 mmol), and TAF (4 mL) using a similar procedure to that described for compound 0206-53 (Example 40): LCMS: 399 [M+1]+; 1H NMR (DMSO-d6) δ 3.61 (s, 3H), 6.72 (m, 5H), 7.51 (d, 1H, J = 6.3 Hz), 7.74 (d, 1H, J = 8.7 Hz).

Step 41c: Propyl 3-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)acetate (Compound 040254)

[0231] The title compound 0402-54 was prepared as a light yellow solid (531 mg, 53%) from compound 020654 (800 mg, 2.01 mmol), 3-bromopropyl acetate (546 mg, 3. 02 mmol) and CS2CO3 (1.11 g, 3.42 mmol) in DMF (36 mL) using a procedure similar to that described for compound 040251 (Example 38): LCMS: 499 [M+1]+.

Step 41d: 3-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propan-1-ol (Compound 0403-54)

[0232] The title compound 0403-54 was prepared as a white solid (412 mg, 85%) from compound 0402-54 (531 mg, 1.066 mmol), and K2CO3K2CO3 (177 mg, 1.279 mmol) in MeOH ( 8.3 mL) using a procedure similar to that described for compound 0403-51 (Example 38): LCMS: 457 [M+1]+.

Step 41e: 3-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propyl methanesulfonate (Compound 0404-54)

[0233] The title compound 0404-53 was prepared as a white solid (260 mg, 54%) from compound 0403-54 (412 mg, 0.905 mmol), and NEt3 (275 mg, 2.716 mmol) and MsCl ( 156 mg, 1.358 mmol) using a procedure similar to that described for compound 0404-51 (Example 38): LCMS: 535 [M+1]+.

Step 41f: 2-(2-Iodo-5-methoxyphenylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 54)

[0234] The title compound 54 was prepared as a white solid (18 mg, 165%) from compound 0404-54 (120 mg, 0.225 mmol) in isopropylamine (20 mL) using a procedure similar to that described for the compound 51 (Example 38): LCMS: 498 [M+1]+; 1H NMR (DMSO-d6) δ 0.91 (d, 6H, J = 6.3 Hz), 1.75 (m, 2H), 2.43 (t, 2H, J = 5.7 Hz), 2.59 (m, 1H), 3.58 (s , 3H), 4.23 (t, 2H, J = 7.2 Hz), 6.32 (d, 1H, J = 2.7 Hz), 6.44 (s, 2H), 6.68 (dd, 1H, J1 = 3.0 Hz, J2 = 9.0 Hz ), 6.85 (d, 1H, J = 6.3 Hz), 7.75 (m, 2H).

Example 42: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(neopentylamino)propyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 56) Step 42a: 2-(3-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl) propyl)isoindoline-1,3-dione (Compound 0302-56)

[0235] The title compound 0302-56 was prepared as a pale yellow solid (410 mg, 57%) from the compound 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H -imidazo[4,5-c]pyridin-4-amine (Compound 0206-3) (500 mg, 1.2 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (610 mg, 2, 4mmol) and CS2CO3 (652mg, 2.0mmol) in anhydrous DMF (8.5mL) using a procedure similar to that described for compound 0302-32 (28): LC-MS: 599.7 [M+1]+; 1H NMR (DMSO-d6): δ 1.93 (m, 2H), 3.61 (t, J= 6.6 Hz, 2H), 4.21 (t, J= 8.1 Hz, 2H), 6.04 (s, 2H) , 6.40 (s, 2H), 6.50 (s, 1H), 6.87 (d, J= 6.0 Hz, 1H), 7.21 (s, 1H), 7.70 (d, J= 6.0 Hz, 1H) , 7.85 (s, 4H).

Step 42b: 1-(3-Aminopropyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0303 -56)

[0236] The title compound 0303-56 was prepared as a pale yellow solid (200 mg, 74%) from compound 0302-56 (350 mg, 0.58 mmol), and N2H4-H2O (580 mg, 11 .6 mmol) in CH2Cl2 (7.0 mL) in EtOH (0.6 mL) using a procedure similar to that described for compound 0303-32 (Example 28): LC-MS: 469.7 [M+1]+.

Step 42c. 2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(neopentylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 56 )

[0237] The title compound 54 was prepared as a white solid (110mg, 37%) from compound 0303-56 (257mg, 0.55mmol), and pivalaldehyde (60mg, 0.70mmol), using a procedure similar to that described for compound 33 (Example 29): m.p. 170 ~ 174 oC. LCMS: 540 [M+1]+; 1H NMR (DMSO-d6): δ 0.84 (s, 9H), 1.76 (m, 2H), 2.14 (s, 2H), 2.43 (t, J = 6.9 Hz, 2H), 4.23 (t, 2H), J = 7.2 Hz, 2 H), 6.04 (s, 2 H), 6.36 (s, 2 H), 6.63 (s, 1 H), 6.80 (d, J = 6.0 Hz, 1 H), 7.47 (s, 1H), 7.71 (d, J=6.0Hz, 1H).

Example 43: Preparation of 1-(3-(tert-butylamino)propyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin -4- amine (Compound 58)

[0238] The title compound 58 was prepared as a white solid (64 mg, 37%) from the compound 3-(4-amino-2(6-iodobenzo[d][1,3]ioxol-5-ylthio )-1H-imidazo[4,5-c]pyridin-1-yl)propyl methanesulfonate (0404-52 (180 mg, 0.328 mmol) in tert-butylamine (20 mL) using a procedure similar to that described for compound 51 ( Example 38): m.p. 224 ~ 227 oC. LCMS: 526 [M+1]+; 1H NMR (DMSO-d6): δ 0.95 (s, 9H), 1.71 (m, 2H), 2.38 (t, J = 7.2 Hz, 2 H), 4.23 (t, J = 7.2 Hz, 2 H), 6.04 (s, 2H), 6.37 (s, 2 H), 6.64 (s, 1 H), 6.82 (d, J = 6.0 Hz, 1H), 7.48 (s, 1H), 7.72(d, J = 6.0 Hz, 1H).

Example 44: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(pentan-3-ylamino)propyl)-1H-imidazo[4,5-c ] pyridin-4-amine (Compound 60)

[0239] For a solution of 1-(3-aminopriol)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(pentan-3-ylamino)propyl) -1H-imidazo[4,5-c]pyridin-4-amine (Compound 0303-56) (150 mg, 0.32 mmol) in menthol (6 mL) was added 3-pentanone (33 mg, 0.38 mmol). ). After stirring for 30 minutes at room temperature, NaBH3CH (80 mg, 1.28 mmol) was slowly added. Traces of CH3COOH were added and the mixture was stirred overnight. The reaction was quenched by addition of saturated NaHCO3 (10 mL). The mixture was diluted with water (100 ml) and extracted with dichloromethane (50 ml x 2). The extract was concentrated and purified by pre-HPLC to give the title compound 60 as a white solid (34 mg, 20%): m.p. 164 ~ 166 oC. LCMS: 540 [M+1]+; 1H NMR (DMSO-d6): δ 0.80 (s, 9H), 1.29 (m, 4H), 2.21 (m, 1H), 2.43 (t, J = 6.3 Hz, 2H), 4.24 (t, J = 6.9 Hz, 2 H), 6.05 (s, 2 H), 6.40 (s, 2 H), 6.64 (s, 1 H), 6.83 (d, J = 5.7 Hz, 1 H), 7.49 (s, 1 H) H), 7.72 (d, J = 5.7 Hz, 1H).

Example 45: Preparation of 2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(2-isopropoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine ( Compound 61)

[0240] For a solution of 2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(2-isopropoxyethyl)-1H-imidazo[4,5-c]pyridin-4- amine (Compound 0206-22) (500mg, 1.37mmol), PPh3 (718mg, 2.74mmol), 2-isopropoxyethanol (185mg, 1.78mmol) and DIAD (830mg, 4.11mmol ) in toluene (12 mL) and CH2Cl2 (3 mL), was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (30/1 CH 2 Cl 2 /MeOH) and followed by pre-HPLC to give the title compound 61 as a white solid (113 mg, 18 %): m. P. 183 ~ 190 oC. LCMS: 451 [M+1]+; 1H NMR (DMSO-d6) δ 0.94 (d, 6H, J = 5.4 Hz), 3.45 (m, 1H), 3.64 (t, 2H, J = 7.5 Hz), 4.51 (t, 2H, J = 3.9 Hz) , 6.12 (s, 2H), 7.02 (s, 1H), 7.28 (d, 1H, J = 7.5 Hz), 7.40 (s, 1H), 7.74 (d, 1H, J = 6.6 Hz), 8.57 (s, 2H), 13.28 (s, 1H).

Example 46: Preparation of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-isopropoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine ( Compound 62)

[0241] The title compound 62 was prepared as a white solid (100mg, 28%) from 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2 -isopropoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-3) (300 mg, 0.727 mmol), PHh3 (381 mg, 1.46 mmol), 2-isopropoxyethanol (98, 5 mg, 0.946 mmol) and DIAD (441 mg, 2.18 mmol) in toluene (6 mL) and CH2Cl2 (1.5 mL), using a procedure similar to that described for the title compound 61 (Example 45): m . P. 195 ~ 201 oC. LCMS: 499 [M+1]+; 1H NMR (DMSO-d6) δ 0.95 (d, 6H, J = 6.6 Hz), 3.45 (m, 1H), 3.64 (t, 2H, J = 5.1 Hz), 4.49 (t, 2H, J = 5.1 Hz) , 6.09 (s, 2H), 6.99 (s, 1H), 7.27 (d, 1H, J = 6.9 Hz), 7.52 (s, 1H), 7.73 (d, 1H, J = 7.5 Hz), 8.49 (s, 2H), 13.12 (s, 1H).

Example 47: Preparation of 2-(2-iodo-5-methoxyphenylthio)-1-(2-isopropoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 64)

[0242] For the title compound 64 was prepared as a white solid (20 mg, 8.2%) from the compound 2-(2-iodo-5-methoxyphenylthio)-1-(2-isopropoxyethyl)-1H- imidazo[4,5-c]pyridin-4-amine (Compound 0206-54) (200 mg, 0.50 mmol), PPH3 (263 mg, 1.00 mmol), 2-isopropoxyethanol (68 mg, 0.65 mmol) and DIAD (304 mg, 1.51 mmol) in toluene (5 mL) and CH2Cl2 (1 mL) using a procedure similar to that described for compound 61 (Example 45): m. P. 102 ~108 oC. LCMS: 485 [M+1]+; 1H NMR (DMSO-d6) δ 0.89 (d, 6H, J = 6.9 Hz), 3.38 (m, 1H), 3.56 (t, 2H, J = 5.4 Hz), 3.60 (s, 3H), 4.35 (t, 2H, J = 4.5 Hz), 6.39 (m, 3H), 6.67 (dd, 1H, J1 = 2.1 Hz, J 2 = 8.1 Hz), 6.83 (d, 1H, J = 6.0 Hz), 7.74 (m, 2H ).

Example 48: Preparation of 4-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanamide (Compound 66) Step 48a: Ethyl 4-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanoate ( Compound 0502-66)

[0243] A mixture of 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-3) (200 mg, 0.485 mmol), ethyl-4-bromobutanoate (142 mg, 0.728 mmol), CS2CO3 (268 mg, 0.825 mmol) in DMF (7 mL) was stirred at 85°C for 2 hours. DMF was evaporated in vacuo and the residue was purified by silica gel column chromatography (100:1 methylene chloride/methanol) to give the title compound 0502-66 as a white solid (168 mg, 66%): LCMS : 527 [M+1]+.

Step 48b: 4-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanamide(Compound 66)

[0244] Compound 0502-66 (180 mg, 0.342 mmol) was dissolved in 5 mL of ammonia in methanol (40%, w/w) and the mixture was stirred at 50°C in a sealed tube overnight. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (40:1 methylene chloride/methanol) to give the title compound 66 as a white solid (68 mg, 40%): m.p. 227 ~ 232 °C, LCMS: 498 [M+1]+; 1H NMR (DMSO-d6) δ 1.84 (m, 2H), 2.06 (t, 2H, J = 7.2 Hz), 4.17 (t, 2H, J = 7.2 Hz), 6.05 (s, 2H), 6.39 (s, 2H), 6.68 (s, 1H), 6.81 (m, 2H), 7.28 (s, 1H), 7.47 (s, 1H), 7.71 (d, 1H, J = 6.0 Hz).

Example 49: Preparation of 5-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanamide (Compound 68) Step 49a: Methyl 5-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanoate ( Compound 0502-68)

[0245] The title compound 0502-68 was prepared as a white solid 9131 mg, 51%) from the compound 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo [4,5-c] pyridin-4 amine (Compound 0206-3) (200 mg, 0.485 mmol), methyl-5-bromopentanoate 9142 mg, 0.728 mmol), CS2CO3 (268 mg, 0.825 mmol) in DMF (8 mL ) using a procedure similar to that described for compound 0502-66 (Example 48): LCMS: 527 [M+1]+; 1H NMR (DMSO-d6) δ 1.47 (m, 2H), 1.63 (m, 2H), 2.28 (t, 2H, J = 7.5 Hz), 3.54 (s, 3H), 4.17 (t, 2H, J = 6.9 Hz), 6.05 (s, 2H), 6.38 (s, 2H), 6.66 (s, 1H), 6.80 (d, 1H, J = 6.0 Hz), 7.48 (s, 1H), 7.71 (d, 1H, J = 5.7 Hz).

Step 49b: 5-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanamide (Compound 68)

[0246] Title compound 68 was prepared as a white solid (38 mg, 30%) from compound 0502-68 (131 mg, 0.249 mmol) and 10 mL of ammonia in methanol (40%, w/w) using a procedure similar to that described for compound 0502-66 (Example 48): m.p. 203 ~ 210 °C, LCMS: 512 [M+1]+; 1H NMR (DMSO-d6) δ 1.44 (m, 2H), 1.62 (m, 2H), 2.02 (t, 2H, J = 7.2 Hz), 4.16 (t, 2H, J = 6.9 Hz), 6.06 (s, 2H), 6.52 (s, 2H), 6.70 (m, 2H), 6.84 (d, 1H, J = 5.7 Hz), 7.23 (s, 1H), 7.49 (s, 1H), 7.71 (d, 1H, J = 6.0 Hz).

Example 50: Preparation of 6-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)hexanamide (Compound 70) Step 50a: Ethyl 6-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)hexanoate ( Compound 0502-70)

[0247] The title compound 0502-70 was prepared as a white solid (200 mg, 30%) from the compound 2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H- imidazo[4,5-c]pyridin-4-amine (Compound 0206-3) (500 mg, 1.2 mmol), ethyl methyl-6-bromohexanoate (401 mg, 1.8 mmol), CS2CO3 (670 mg, 2.1 mmol) in DMF (18 mL) using a procedure similar to that described for compound 0502-66 (Example 48): LCMS: 555 [M+1]+.

Step 50b: 6-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)hexanamide(Compound 70)

[0248] Title compound 70 was prepared as a white solid 935 mg, 18%) from compound 0502-70 (200 mg, 0.36 mmol) and 28 mL of ammonia in methanol (40%, w/w ) using a procedure to that described for compound 0502-66 (Example 48): m.p. 194 ~ 198°C, LCMS: 526 [M+1]+; 1H NMR (DMSO-d6) δ 1.20(m, 2H) 1.41 (m, 2H), 1.57 (m, 2H), 1.96 (t, 2H, J = 7.8 Hz), 4.14 (t, 2H, J = 7.4 Hz ), 6.05 (s, 2H), 6.38 (s, 2H), 6.68 (2, 2H), 6.81 (d, 1H, J = 5.7 Hz), 7.19 (s, 1H), 7.48 (s, 1H), 7.71 (d, 1H, J = 6.0 Hz).

Example 51: Preparation of N-(2-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1- yl)ethyl)acetamide (Compound 72)

[0249] Compound 32 (200mg, 0.44mmol) in Net3 (0.1mml, 0.66mmol) was dissolved in dichloromethane (10ml) and cooled to 0°C with an ice water bath. To this cooled solution, acetyl chloride (38 mg, 0.48 mmol) was added dropwise. The solution was stirred at 0°C for 0.5 hours and then the solvent was removed under reduced pressure. The residue was purified by pre-HPLC to give the title compound 72 as a white solid (47 mg, 22%): m.p. 193~197°C, LC-MS: 498 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 1.67 (s, 3H), 3.32 (m, 2H), 4.21 (t, 2H, J = 5.6 Hz), 6.02 (s, 2H), 6.29 (s, 2H) , 6.70 (s, 1H), 6.71 (d, 1H, J = 5.7 Hz), 7.43 (s, 1H), 7.68 (d, 1H, J = 5.7 Hz), 7.97 (t, 1H, J = 6.0 Hz) .

Example 52: Preparation of N-(3-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1- yl)propyl)acetamide (Compound 74)

[0250] A suspension of 1-(3-aminopropyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0303-56) (190 mg, 0.41 mmol) in acetic acid (1.4 mL) was cooled to 0°C. To this cooled solution was added acetic anhydride (124 mg, 1.23 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (8 mL) and the solvent was removed under reduced pressure to leave a residue which was purified by pre-HPLC to give the title product 74 as a white solid (90 mg, 43%): m.p. 102~104°C, LC-MS: 512.0 (M+H+). 1H NMR (300 MHz, DMSO-d6) δ 1.77 (m, 5H), 3.01 (m, 2H), 4.16 (t, 2H, J= 7.5 Hz), 6.05 (s, 2H), 6.36 (s, 2H) , 6.62 (s, 1H), 6.80 (d, 1H, J= 5.7 Hz), 7.47 (s, 1H), 7.71 (d, 1H, J= 6.0 Hz), 7.90 (t, 1H, J= 4.5 Hz) .

Example 53: Preparation of N-(4-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1- yl)butyl)acetamide (Compound 76) Step 53a: 2-(4-(4-Amino-2-(6-iodobenzo[d][1,3]dioxo-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl) butyl)isoindoline-1,3-dione (Compound 0302-76)

[0251] A mixture of 2-(6-iodobenzo[d][1,3]dioxo-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butyl)isoindoline-1,3 - dione (Compound 0206-3) (412 mg, 1.0 mmol), 2-(4-bromobutyl)isoindoline-1,3-dione (620 mg, 2.2 mmol), CS2CO3 (814 mg, 2.5 mmol) in anhydrous DMF (6 mL) was heated to 85°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and filtered. The DMF solvent was removed under high vacuum to give the crude product as an orange solid which was purified by silica gel column chromatography (CH2Cl2/MeOH/Net3=100/1/0.05) to give the title compound 0302 -76 as a pale yellow solid (482 mg, 79%): LC-MS: 614 [M+1]+.

Step 53b: 1-(4-Aminobutyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0303 -76)

[0252] A mixture of compound 0302-76 (470 mg, 0.77 mmol) and N2H4-H2O (767 mg, 15.34 mmol) in CH2Cl2 (10.0 mL) and ethanol (1.0 mL) was heated at 50°C and stirred for 1.5 hours. The solvent was removed under reduced pressure and H2O (25mL) was added. The mixture was extracted with CH2Cl2 (30 mL x 3). The combined organic layer was washed with H 2 O (12 mL x 2), dried over Na 2 SO 4 , filtered and evaporated to give the title compound 0303-76 as a pale yellow solid (240 mg, 65%): LC-MS: 483.7 ( M+H+).

Step 53c: N-(4-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl) butyl)acetamide (Compound 76)

[0253] A suspension of 0303-76 (240 mg, 0.5 mmol) in acetic acid 91.6 mL) was cooled to 0°. To this cooled solution was added acetic anhydride (204 mg, 2.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with CH2Cl2 (10 mL) and the solvent was removed under reduced pressure. The resulting residue was purified by pre-HPLC to give the title compound 76 as a white solid (70 mg, 27%): m.p. 198~201°C, LC-MS: 526.0 (M+H+). 1H NMR (300 MHz, DMSO-d6) δ 1.33 (m, 2H), 1.69 (m, 2H), 2.97 (m, 2H), 4.16 (t, 2H, J= 7.2 Hz), 6.05 (s, 2H) , 6.36 (s, 2H), 6.66 (s, 1H), 6.80 (d, 1H, J= 5.7 Hz), 7.48 (s, 1H), 7.70 (d, 1H, J= 5.7 Hz), 7.78 (t, 1H, J=4.5 Hz).

Example 54: Preparation of 2-(6-chlorobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 77) Step 54a: 2-(2-(4-Amino-2-(6-chlorobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl) ethyl)isoindoline-1,3-dione (Compound 0302-77)

[0254] A mixture of 0206 (2.5 g, 7.8 mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (0301)(3.0 mg, 11.7 mmol) and CS2CO3 ( 4.3 g, 2.1 mmol) in anhydrous DMF (28 mL) was stirred at 85°C for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under high vacuum to give the crude product as an orange solid which was purified by silica gel column chromatography CH2Cl2/MeOH=100/1) to provide compound 0302-77 (1.5 g, 39%) as a pale yellow solid: LC-MS: 494 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 3.93 (t, 2H, J = 5.2 Hz), 4.52 (t, 2H, J = 5.2 Hz), 6.05 (s, 2H), 6.60 (m, 3H), 6.83 (d, 1H, J = 6.0 Hz), 6.99 (s, 1H), 7.66 (d, 1H, J = 6.0 Hz), 7.76 (m, 4H).

Step 54b: 1-(2-Aminoethyl)-2-(6-chlorobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (0303- 77)

[0255] A mixture of 0302-77 (1.5 mg, 3 mmol) and N2H4-H2O (1.8 g, 85%, 85.5 mmol) CH2Cl2 (50 mL) and EtOH (5 mL) was heated to 50°C and stirred for 3 hours. The solid was filtered off and the filtrate was washed with brine (100 mL x 2). The organic layer was dried over Na 2 SO 4 , filtered and concentrated to give the title product 0303-77 (850 mg, 77%) as an orange solid: LC-MS: 364 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 1.98 (s, 2H) 2.80 (m, 2H), 4.18 (t, 2H, J = 6.4 Hz), 6.09 (s, 2H), 6.31 (s, 2H), 6.76 (s, 1H), 6.84 (d, 1H, J = 5.6 Hz), 7.24 (s, 1H), 7.69 (d, 1H, J = 5.6 Hz).

Step 54c: 2-(6-Chlorobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 77)

[0256] To a solution of 0303-77 (850 mg, 2.34 mmol) in methanol (33 mL) was added pivalaldehyde (242 mg, 2.8 mmol). After stirring for 30 minutes at room temperature, NaBH 3 CN (588 g, 9.36 mmol) was slowly added, and the mixture was stirred for another 30 minutes. The mixture was diluted with water (500 ml) and extracted with dichloromethane (100 ml x 2). The extract was concentrated and purified by silica gel column chromatography (CH2Cl2/MeOH=50/1) and crystallization (CH2Cl2/Et2O=1/4) to give the title compound 77 (195 mg, 19%) as a solid. light yellow: m.p. 160 ~ 161 oC. LCMS: 434 [M+1]+; 1H NMR (DMSO-d6) δ 0.76 (s, 9H), 1.60 (s, 1H), 2.17 (s, 2H), 2.76 (m, 2H), 4.24 (t, 2H, J = 6.0 Hz), 6.07 (s, 2H), 6.32 (s, 2H), 6.68 (s, 1H), 6.83 (d, 1H, J = 6.0 Hz), 7.24 (s, 1H), 7.70 (d, 1H, J = 5.6 Hz) .

Example 55: Preparation of 2-(6-Methylbenzo[d][1,3]dioxo-1-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin - 4-amine (Compound 78) Step 55a: 5-Iodo-6-methylbenzo[d][1,3]dioxol (Compound 010778)

[0257] NIS (6.6 g, 29.4 mmol) was added into a solution of Compound 3,4-methylene-dioxyl)toluene (5 g, 36.7 mmol) in MeCN (250 ml). To this mixture was added TFA (8.35 g, 73.4mmol). The mixture was stirred overnight at room temperature. The solution was concentrated to a residue which was purified by column chromatography on silica to provide compound 0107-78 (12.3 g, 63%) as a red liquid. 1H NMR (DMSO-d6): δ 2.26 (s, 3H ), 5.99 (s, 2H), 6.94 (s, 1H), 7.30 (s, 1H).

Step 55b: 1-(4-Methoxybenzyl)-2-(6-methylbenzo[d][1,3]dioxo-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205 -78)

[0258] A mixture of compound 0204 (12.86g, 10mmol), compound 0107-78 (3.14g, 12mmol), NaOt-Bu (960mg, 10mmol), neocuproine hydrate (208mg, 1 mmol) and CuI (190 mg, 1 mmol) in dry DMF (60 ml) was stirred at 110°C overnight. The mixture was concentrated and purified by silica gel column chromatography (CH 2 Cl 2 /MeOH = 100/1) to provide compound 0205-78 (2.0 g, 48%) as an orange solid. LCMS: 421 [M+1]+; 1H NMR(DMSO-d6): δ 2.26 (s, 3H), 3.69 (s, 3H), 5.38 (s, 2H), 5.98 (s, 2H), 6.80 (m, 7H), 7.05 (d, J = 8 Hz, 2H), 7.66 (s, 1H).

Step 55c: 2-(6-Methylbenzo[d][1,3]dioxo-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-78)

[0259] A mixture of compound 0205-78 (2.0g, 4.76mmol) and CF3COOH (20ml) was stirred at 85°C for 4 hours. The mixture was concentrated and diluted with water (50 ml). The resulting solid was collected to provide the title compound 020678 (1.4 g, 78%) as a brown solid: LCMS: 301 [M+1]+; 1H NMR(DMSO-d6): δ 2.28 (s, 3H), 6.06 (s, 2H), 6.87 (s, 2H), 7.02 (s, 1H), 7.15 (s, 1H), 7.58 (s, 1H) , 7.93 (s, 1H), 12.98 (s, 1H).

Step 55d: 2-(2-(4-Amino-2-(6-methylbenzo[d][1,3]dioxo-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl) ethyl)isoindoline-1,3-dione (Compound 0302-78)

[0260] A mixture of compound 0206-78 (1.4 g, 7.00 mmol), and CS2CO3 (2.58 g, 7.93 mmol) in DMF (40 ml) was stirred for 4 hours at 80°. The reaction was filtered and the filtrate was concentrated. The product was purified by column chromatography (dichloromethane/methanol = 20/1) to provide the title compound 0302-78 (760 mg, 34%) as a brown solid: LCMS: 474 [M+1]+; 1H NMR(DMSO-d6): δ 2.12 (s, 3H), 3.90 (t, J = 5.4 Hz, 2H), 4.44 (t, J = 5.4 Hz, 2H), 5.96 (s, 2H), 6.59 (s , 2H), 6.78 (t, 3H), 7.61 (d, J = 5.6 Hz, 1H), 7.78 (m, 4H).

Step 55e: 1-(2-Aminoethyl)-2-(6-methylbenzo[d][1,3]dioxo-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0303 -78)

[0261] To a mixture of H2NNH2 H2O (800mg, 16.1mmol) in dichloromethane/methanol (30ml, 10:1) was added compound 0302-78 (760mg, 1.61mmol). The mixture was stirred for 4 hours at room temperature and then filtered. The filtrate was washed with brine and the organic phase was concentrated to provide the title compound 0303-78 (500 mg, 90%) as an orange solid: LCMS: 344 [M+1]+; 1H NMR (DMSO-d6): δ 1.93 (br, 2H), 2.32 (s, 3H), 2.75 (t, J = 6.4 Hz, 2H), 4.11 (t, J = 6.8 Hz, 2H), 5.99 (s , 2H), 6.16 (s, 2H), 6.79 (m, 2H), 6.93 (s, 1H), 7.64 (d, J = 5.6 Hz, 1H).

Step 55f: 2-(6-Methylbenzo[d][1,3]dioxo-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 78)

[0262] NaBH 3 CN (366mg, 5.82mmol) was added to a solution of compound 0303-78 (500mg, 1.46mmol) and pivalaldehyde (151mg, 1.75mmol) in methanol (20ml). The mixture was stirred for 0.5 hour at room temperature. Dichloromethane (40 ml) was added into the above mixture and washed with brine 3 times. The organic phase was dried over MgSO4 and concentrated to give the crude product which was purified by column chromatography (dichlormethane/methanol = 20/1) and followed by recrystallization from dichloromethane and ether to provide the title compound 78 (30 mg, 5 %) as a white solid: mp 155-156°C; LCMS: 344 [M+1]+; 1H NMR(DMSO-d6) δ 0.76 (s, 9H), 2.17 (s, 2H), 2.33 (s, 3H), 2.70 (t, J = 6.2 Hz, 2H), 4.18 (t, J = 6.2 Hz, 2H), 5.98 (s, 2H), 6.20 (s, 2H), 6.78 (t, 2H), 6.93 (s, 1H), 7.65 (d, J = 5.6 Hz, 1H).

Example 56: Preparation of 2-(6-(methylthio)benzo[d][1,3]dioxo-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c] pyridin-4-amine (Compound 87) Step 56a: 5-(Methylthio)benzo[d][1,3]dioxol (Compound 0106-87)

[0263] To a suspension of magnesium turnings (2.225 g, 93.7 mmol) in anhydrous THF (50 mL) was added dropwise 5-bromo-1,3-benzodioxol (15.03 g, 75.1 mmol) for 1.5 hours under a nitrogen atmosphere. After being heated under reflux for 1 hour, the mixture was cooled to -45°C and quenched with sulfur (2.43 g, 75 mmol) was added thereto. The mixture was stirred at -45°C for 1.5 hours and then at room temperature for 1.5 hours, in which time water (4.1 mL) and 6M HCl (22.5 mL) were added to this solution. Then without purification the reaction pH was adjusted to 7.5, then CH3Cl2, and the crude product was purified by silica gel column chromatography (PE = 100%) to provide the title product 0106-87 (7.034g, 55.8 %) as a white soil: 1H NMR (400 MHz, DMSO-d6) δ 2.41(s, 3H), 5.99(s, 2H), 6.75(q,1H , J= 2 Hz, 8 Hz), 6.86(d ,1H,J = 8 Hz), 6.92(d, 1H, J = 1.6 Hz).

Step 5 6b: 5-iodo-6-(methylthio)benzo[d][1,3]dioxol (Compound 0107-87)

[0264] A mixture of 0106-87 (9.034g, 53.8mmol), HNO3 (5.4ml), (CH3CO)2° (108ml) was stirred at -10°C for 2 hours. The reaction was then poured into ice water for 0.5 hours. The resulting yellow solid was collected to provide 5-(methothio)-6-nitrobenzo[d][1,3]dioxol (6.2 g, 54.3%): LCMS: 214 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 2.49(s,3H), 6.25(s,2H), 7.12 (s, 1H), 7.79(s, 1H).

[0265] A mixture of 5-(methothio)-6-nitrobenzo[d][1,3]dioxol (6.2, 29.2 mmol), Fe 916.36 g, 29.2 mmol), HCl (11 .68 ml) in EtOH (73 ml) and H 2 O (180 ml) was stirred at 110°C for 2 hours. The reaction mixture was adjusted to pH 11 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give 6-(methylthio)benzo[d](1,3]dioxol-5-amine as a liquid dark (3.6 g, 67.3%): LCMS: 184 [M+1]+ ; 1H NMR (400 MHz, DMSO-d6) δ 2.3(s,3H), 5.05(s,2H), 5.86(s, 2H) 6.39 (s, 1H), 6.83(s, 1H).

[0266] To the above prepared 6-(methylthio)benzo[d](1,3]dioxol-5-amine 3.6 g) was added into the mixture of H2SO4 (8.07 ml), CH3CN (150 ml ) and AcOH (225 ml) in water 9150 ml) at 0°C. The mixture was stirred until a clear solution began. To this solution was added NaNO2 (1.495 g) at 0°C. the mixture was warmed to room temperature and allowed to stir at room temperature for 30 minutes. The solution was slowly dropped into a solution of KI (9.811 g) in water 9150 ml) at 50°C, cooled to room temperature to leave a black solid which was purified by silica gel column chromatography (petroleum ether) to obtain the title compound 0107-87 (3.4g, 58.8%). 1H NMR (400 MHz, DMSO-d6) δ 2.3(s, 3H), 6.05 (s, 2H), 6.94(s, 1H), 7.38 (s, 1H).

Step 56c: 1-(4-Methoxybenzyl)-2-(6-(methylthio)benzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205-87)

[0267] Title compound 0205-87 was prepared (1.1 g, 65.3%) as a brown solid from compound 0204 (943 mg, 3.4 mmol), 0107-87 (2 g, 6 .8 mmol), neocuproin hydrate (71 mg, 3.4 mmol), CuI (64.7 mg, 3.4 mmol) and NaOt-Bu (490 mg, 5.1 mmol) in anhydrous DMF (50 mL) using a procedure similar to that described for compound 0205-78 (Example 55): LCMS: 453 [M+1]+; 1H NMR (DMSO-d6) δ 3.68 (s, 3H), 5.37 (s, 2H), 6.00 (s, 2H), 6.45 (s, 2H), 6.64 (s, 1H), 6.81 (d, 2H, J = 9.2 Hz), 6.94(s, 1H), 7.04 (d, 2H, J = 9.2 Hz), 7.65 (s, 1H).

Step 56d: 2-(6-(Methylthio)benzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-87)

[0268] Title compound 0206-87 was prepared (879mg, 100%) as a yellow solid from compound 0205-87 (1.1g, 2.45mmol) and TFA (15ml) using a similar procedure to that described for compound 0206-78 (Example 55): (Example 55): LCMS: 333 [M+1]+; 1H NMR (DMSO-d6) δ 2.40(s, 3H), 6.09 (s, 2H), 6.74 (d, 1H, J =6.8 Hz), 7.03 (s, 1H), 7.11 (s, 3H), 7.53 (d, 1H, , J = 5.6 Hz).

Step 56e: tert-Butyl-2-(4-amino-2-(6-(methylthio)benzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin- 1-yl) ethylcarbamate (Compound 0305-87)

[0269] A mixture of 0206-87 (879 g, 2.65 mmol), tert-butyl-2-bromoethylcarbamate (891 mg, 3.975 mmol) and CS2CO3 (1.464 g, 4.5 mmol) in anhydrous DMF (25 ml ) was heated to 80°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to remove the DMF under high vacuum to give the crude product as an orange solid which was purified by silica gel column chromatography (CH2Cl2/MeOH=50/1) to provide the title Compound 0305-87 (372mg, 29.5%) as a yellow solid: LC-MS: 476 [M+1]+ ; 1H NMR (400 MHz, DMSO-d6) δ 1.26(s,9H), δ 2.43 (s, 3H), 3.22(t,2H, J = 6.6 Hz) 4.18 (t, 2H, J = 6.6 Hz), 6.03 (s, 2H), 6.83 (t, 2H, J = 5 Hz), 6.96(s, 1H), 7.08 (s, 1H), 7.67(d, 1H, J = 5 Hz).

Step 56f: 1-(2-Aminoethyl)-2-(6-(methylthio)benzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0303-87)

[0270] A mixture of TFA (1.8 ml) and compound 0305-87 (372 mg, 995 mmol) in CH 2 Cl 2 (10 ml) was stirred at room temperature for 2 hours. A saturated NaHCO3 solution was added and it was then extracted with dichloromethane. The organic phase was isolated and evaporated to obtain the title compound 0308-87 as a solid (260 mg, 88.7%): LCMS: 376 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 2.45 (s, 3H), 2.793(t, 3H, J = 6.6Hz) 4.18 (t, 2H, J = 6.6 Hz), 6.04 (s, 2H), 6.24 ( s, 2H), 6.77 (s, 1H), 6.82 (d, 1H, J = 6.0 Hz), 7.02 (s, 1H), 7.67 (d, 1H, J = 6 Hz).

Step 56g: 2-(6-(Methylthio)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin- 4-amine (Compound 87)

[0271] To a solution of compound 0303-87 (245 mg, 65.3 mmol) in methanol (15 mL) was added pivaaldehyde (84.41 g, 980 mmol). After stirring for 30 minutes at room temperature, NaBH3CN (164.14 mg, 2.612 mmol) was slowly added, and the mixture was stirred for another 30 minutes. The mixture was diluted with water (500 ml) and extracted with dichloromethane (500 ml x 2). The extract was concentrated and purified by silica gel column chromatography (CH2Cl2/MeOH = 50/1) and crystallization (CH2Cl2 / Et2O =1/4) to give the title compound 87 (52 mg, 17.9%) as a solid. white: m.p. 170 ~ 170 oC. LCMS: 446 [M+1]+; 1H NMR (DMSO-d6) δ 0.75 (s, 9H), 1.56 (s, 1H), 2.16 (s, 2H), 2.43(s, 2H), 2.72(s, 2H), 4.22 (t, 2H) , 6.02 (s, 2H), 6.25 (s, 2H), 6.68 (s, 1H), 6.79 (d, 1H, J = 5.2 Hz), 7.01 (s, 1H), 7.66 (d, 1H, J = 5.2 Hz).

Example 57: Preparation of 2-(6-Methoxybenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 79) Step 57a: 5-Methoxybenzo[d][1,3]dioxol (Compound 0106-79)

[0272] NaOH (1.2 g, 30 mmol) was added into a solution of sesamol (2.76 g, 20 mmol) in methanol (15 ml) at 0°C. The mixture was stirred for 1 hour at 0°C and then MeI (3.41 g, 24 mmol) was added dropwise into the above solution. The reaction mixture was stirred for 3 hours at room temperature. The solution was concentrated and purified by column chromatography (petroleum ether) to give compound 0106-79 (2.5 g, 82%) as a colored liquid: (1H NMR (DMSO-d6) δ 3.67 (s, 3H ), 5.94 (s, 2H), 6.33 (dd, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H).

Step 57b: 5-Iodo-6-methoxybenzo[d][1,3]dioxol (Compound 010779)

[0273] To a mixture of NIS (3.38g, 15mmol) and compound 0106-79 (2.28g, 15mmol) in MeCN (100ml) was added TFA (3.42g, 30mmol) . The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and purified by silica column chromatography (petroleum ether) to provide the title compound 0107-79 (3.3 g, 79%) as a white solid: 1H NMR (DMSO-d6) δ 3.74 (s, 3H), 5.60 (s, 2H), 6.85 (s, 1H), 7.27 (s, 1H).

Step 57c: 2-(6-Methoxybenzo[d][1,3]dioxol-5-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0205 -79)

[0274] Title compound 0205-79 was prepared (800 mg, 26%) as a brown solid from compound 0204 (2.0 g, 7 mmol), compound 0107-79 (2.33 g, 8 .4 mmol), NaOt-Bu (672 mg, 7 mmol), neocuproin hydrate (146 mg, 0.7 mmol) and CuI (133 mg, 0.7 mmol) in dry DMF (40 mL) using a similar procedure to that described for compound 0205-78 (Example 55): LCMS: 437 [M+1]+; 1H NMR (DMSO-d6) δ 3.70 (s, 6H), 5.43 (s, 2H), 5.99 (s, 2H), 6.79 (s, 1H), 6.84 (d, 3H), 7.01 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.43 (s, 2H), 7.69 (s, 1H).

Step 57d: 2-(6-Methoxybenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-79)

[0275] Title compound 0206-79 was prepared (570 mg, 98%) as a brown solid from compound 0205-79 (0.8 g, 1.83 mmol) and CF3COOH (10 ml) using a procedure similar to that described for compound 0206-78 (Example 55): LCMS: 317 [M+1]+; 1H NMR (DMSO-d6) δ 3.74 (s, 3H), 6.07 (s, 2H), 6.82(d, 2H), 7.01 (s, 1H), 7.10 (s, 1H), 7.60 (m, 2H), 12.71 (br, 1H).

Step 57e: Tect-Butyl 2-(4-amino-2-(6-methoxybenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl) ethylcarbamate (Compound 0305-79)

[0276] Title compound 0305-79 was prepared 9200mg, 25%) as a brown solid from compound 0206-79 (570mg, 1.8mmol), tert-butyl-2-bromoethylcarbamate (605mg, 2.7 mmol) and CS2CO3 (997 mg, 3.1 mmol) in DMF (15 mL) using a procedure similar to that described for compound 0305-87 (Example 56): LCMS: 460 [M+1]+; 1H NMR (DMSO-d6) δ 1.29 (s, 9H), 3.20 (m, 2H), 3.73 (s, 3H), 4.21 (t, J = 5.6 Hz, 2H), 5.98 (s, 2H), 6.33 ( s, 2H), 6.72 (d, J = 6.0 Hz, 2H), 6.89 (s, 1H), 7.65 (d, J = 6.0 Hz, 1H).

Step 57f: 1-(2-Aminoethyl)-2-(6-methoxybenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0303 -79)

[0277] A solution of compound 0305-79 (1.0g, 2.18 mmol) and TFA (4 mL) in CH2Cl2 (50 mL) was stirred at room temperature for 2 hours. The mixture was adjusted to a pH of 8~9 with a saturated aqueous solution of Na2CO3 and extracted with CH2Cl2. The organic layer was separated and dried over Na2SO4, concentrated to obtain the title compound 0303-79 (734 mg, 93%) which was used directly for the next step without further purification: LCMS: 360 [M+1]+; 1H NMR (DMSO-d6) δ 2.78 (t , J = 6.4 Hz, 2H), 3.71 (m, 2H), 3.75 (s, 3H), 5.99 (s, 2H), 6.23 (s, 2H), 6.70 ( s, 1H), 6.80(d, J=6.0 Hz, 1H), 6.91 (s, 1H), 7.66 (d, J=6.0 Hz, 1H).

Step 57g: 2-(6-Methoxybenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 79)

[0278] To a solution of compound 0303-79 (734 mg, 2.04 mmol) in methanol (40 mL) was added pivalaldehyde (352 mg, 4.08 mmol). After stirring for 30 minutes at room temperature, NaBH3CN (423 mg, 6.7 mmol) was slowly added, and the mixture was stirred for an additional 30 minutes. The mixture was diluted with water (100 ml) and extracted with dichloromethane (100 ml x 2). The extract was concentrated and purified by silica gel column chromatography (CH2Cl2/MeOH = 50/1) and crystallization (CH2Cl2 / Et2O =1/4) to give the title Compound 79 (151 mg, 17%) as a yellow solid : m.p. 164 ~ 167 oC. LCMS: 430 [M+1]+; 1H NMR (DMSO-d6) δ 0.78 (s, 9H), 2.19 (s, 2H), 2.74 (t, J = 6.0 Hz, 2H), 3.76 (s, 3H), 4.25 (t, J = 6.0 Hz , 2H), 5.99 (s, 2H), 6.25 (s, 2H), 6.66 (s, 1H), 6.81 (d, J = 6.0 Hz, 1H), 6.92 (s, 1H), 7.68 (d, J = 6.0 Hz, 1H).

Example 58: Preparation of 2-(6-tert-butylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin -4-amine (Compound 86) Step 58a: 5-tert-Butylbenzo[d][1,3]dioxol (Compound 0106-86)

[0279] Aqueous NaOH (8 g, 100 mmol) was slowly added into a solution of 4-tert-butylcatechol (8.3 g, 50 mmol) in DMSO (100 mL) at 90°C. The solution was stirred for 1 hour at 90°C and then CH 2 I 2 (10 ml) was added dropwise into the above solution. The mixture was stirred for 2 hours at 90° and was distilled under reduced pressure to give the title compound 0106-84 (4 g, 45%) as a colored liquid: 1H NMR(400M): (DMSO-d6) δ 1.23 (s, 9H), 5.95 (s, 2H), 6.80 (s, 2H), 6.98 (s, 1H).

Step 58b: 5-tert-Butyl-6-iodobenzo[d][1,3]dioxol (Compound 0107-86)

[0280] HNO3 (4.5 ml) was added into a solution of compound 0106-86 (8g, 45 mmol) in Ac2O (90 ml) at -10°C. the mixture was stirred for 2 hours at -10°C. the pH of the mixture was adjusted to 7-8 with 10% NaOH. Dichloromethane (200 ml) and water (100 ml) were added into the above mixture and it was extracted with dichloromethane three times. The organic phase was dried over MgSO4, filtered and concentrated to give 5-tert-butyl-6-nitrobenzo[d][1,3]dioxol (9.5 g, 95%) as a yellow liquid.1H NMR (400M ): (DMSO-d6) δ 1.29(s, 9H), 6.13 (s, 2H), 7.16 (s, 1H), 7.24 (s, 1H).

[0281] For the above preparation of 5-tert-butyl-6-nitrobenzo[d][1,3]dioxol (1.1 g, 5 mmol), Fe (5.5 g, 100 mmol) and HCl (2 ml) were added into ethanol (6 ml) and water 918 ml). The mixture was stirred for 2 hours at reflux temperature. The pH was adjusted to 7-8 and the mixture was filtered and washed with methanol. The filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate 1%-5%) to give 6-tert-butylbenzo[d][1,3]dioxol-5-amine (240 mg, 25 %) as a red solid. LCMS: 194 [M+1]+; 1H NMR(400M): (DMSO-d6) δ 1.28(s, 9H), 4.46 (s, 2H), 5.77 (s, 2H), 6.32 (s, 1H), 6.63 (s, 1H).

[0282] 6-tert-butylbenzo[d][1,3]dioxol-5-amine (1.55 g, 8.03 mmol) was added to a solution of H2SO4 (5.51 g, 56.22 mmol) in MeCN (60 ml) and water (60 ml) at 0°C. NaNO2 (0.61 g, 8.83 mmol) was then added to the above mixture. The reaction mixture was stirred for 1 hour at 0°C and then a solution of KI (4 g, 24.1 mmol) in water (60 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The resulting solid was collected and purified by column chromatography (petroleum ether) to give the title compound 0107-86 (2.2 g, 90%) as a white solid. 1H NMR(400M): (DMSO-d6) δ 1.44 (s, 9H), 6.00 (s, 2H), 7.01 (s, 1H), 7.46 (s, 1H).

Step 58c: 2-(6-tert-Butylbenzo[d][1,3]dioxol-5-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine ( Compound 0205-86)

[0283] Title compound 0205-78 was prepared (1.8 g, 56%) as a brown solid from compound 0204 (2.0 g, 7 mmol), compound 0107-86 (2.13 g, 7 mmol), NaOt-Bu (672 mg, 7 mmol), neocuproin hydrate (146 mg, 0.7 mmol), and CuI (133 mg, 0.7 mmol) in dry DMF (40 mL) using a similar procedure to that described for compound 0205-78 (Example 55): LCMS: 463 [M+1]+; 1H NMR (DMSO-d6) δ 1.41 (s, 9H), 3.71 (s, 3H), 5.43 (s, 2H), 6.01 (s, 2H), 6.66 (s, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.02 (s, 1H), 7.13 (m, 3H), 7.55 (s, 2H), 7.70 (s, 1H).

Step 58d. 2-(6-tert-Butylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 0206-86)

[0284] Title compound 0206-86 was prepared (1.3 g, 98%) as a brown solid from compound 0205-86 91.8 g, 3.9 mmol) and CF3COOH (20 mL) using a procedure similar to that described for compound 0206-78 (Example 55): LCMS: 343 [M+1]+; 1H NMR (DMSO-d6) δ 1.43 (s, 9H), 6.08 (s, 2H), 6.91 (d, J = 5.6 Hz, 1H), 7.10 (d, 1H), 7.59 (d, J = 6.8 Hz, 1H), 8.40 (s, 2H), 13.11 (s, 1H).

Step 58e: tert-Butyl 2-(4-amino-2-(6-tert-butylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1- yl) ethylcarbamate (Compound 0305-86)

[0285] Title compound 0305-86 was prepared (440 mg, 24%) as a brown solid from compound 0206-86 91.3 g, 3.8 mmol), tert-butyl-2-bromoethylcarbamate 91, 3 g, 5.7 mmol), and CS2CO3 (2.1 g, 6.5 mmol) in DMF (40 mL) using a procedure similar to that described for compound 0305-87 (Example 56): LCMS: 486 [M +1]+; 1H NMR (DMSO-d6) δ 1.27 (s, 9H), 1.50 (s, 9H), 3.25 (d, 2H), 4.20 (s, 2H), 5.98 (s, 2H), 6.32 (s, 2H), 6.67 (s, 1H), 6.75 (d, J = 4.8 Hz, 1H), 7.01 (m, 2H), 7.67 (d, J = 5.2 Hz, 1H).

Step 58f: 1-(2-Aminoethyl)-2-(6-tert-butylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine ( Compound 0303-86)

[0286] Title compound 0303-86 was prepared (349 mg, 95%) from compound 0305-86 (445 g, 0.92 mmol) and TFA (4 mL) in CH2Cl2 (50 mL) using a procedure similar to that described for compound 0303-79 (Example 57): LCMS: 386 [M+1]+; 1H NMR (DMSO-d6) δ 1.50 (s, 9H), 2.78 (t, J = 6.4 Hz, 2H), 3.17 (s, 2H), 4.10 (t, J = 6.4 H, 3H), 5.98 (s, 2H), 6.20 (s, 2H), 6.57 (s, 1H), 6.84(d, J=6.0 Hz, 1H), 7.02 (s, 1H), 7.69 (d, J=6.0 Hz, 1H).

Step 58g: 2-(6-tert-Butylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 86)

[0287] Title compound 86 was prepared 9190 mg, 46%) as a yellow solid from compound 0303-86 (349 mg, 0.9 mmol), pivalladehyde (156 mg, 1.8 mmol) and NaH3CN ( 226 mg, 3.6 mmol) using a procedure similar to that described for compound 79 (Example 57): m.p. 142 ~ 148 oC. LCMS: 456 [M+1]+; 1H NMR (DMSO-d6) δ 0.77 (s, 9H), 1.52 (s, 9H), 2.18 (s, 2H), 2.76 (t, J = 8.4 Hz, 2H), 4.22 (t, J = 8.4 Hz , 2H), 5.97 (s, 2H), 6.34 (s, 2H), 6.51 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H).

Example 59: Preparation of 1-(2-(Neopentylamino)ethyl)-2-(6-vinylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 84) Step 59a: 2,4-Dihydroxy-3-nitropyridine (Compound 0108)

[0288] Vaporized HNO3 (90 mL) was added to a stirred solution of 2,4-dihydroxypyridine (0601) (100 g, 0.9 mol) in concentrated H2SO4 (300 mL) at 0°. After 45 minutes, the solution was poured into compressed ice and the mixture was cooled in a freezer. The resulting precipitate was filtered, washed with cold water, and dried to yield the title compound 0108 (135 g, 96%) as a pale yellow solid: LCMS: 157 [M+1]+; 1H NMR (DMSO-d6) δ 6.05 (d, 1H, J = 7.2 Hz), 7.47 (d, 1H, J = 7.2 Hz), 11.91 (s, 1H), 12.47 (s, 1H).

Step 59b: 2,4-Dichloro-3-nitropyridine (Compound 0109)

[0289] Compound 0108 (10 g, 64 mmol) was dissolved in POCl 3 (70 mL) and heated overnight at 85°C. Excess POCl3 was evaporated at atmospheric pressure. The precipitate was filtered and dried to give the title compound 0109 (9.95 g, 80.5%) as a yellow solid: 1H NMR (CDCl 3 ) δ 7.47 (d, J = 5.7 Hz, 1H), 8.44 (d , J = 5.1 Hz, 1H).

Step 59c: tert-Butyl 2-(2-chloro-3-nitropyridin-4-ylamino)ethylcarbamate (Compound 0602-84)

[0290] A mixture of compound 0109 (55 g, 0.285 mol), tert-butyl-N-(2-aminotheyl)carbamate (59.3 g, 0.37 mol) and Et3N (43.2 g, 0.427 mol) in DMF (450 mL) was heated to 65°C and stirred for 2.5 hours. The DMF was removed under reduced pressure and the residue was poured into brine, extracted with EtOH-water to provide the title compound 060284 (65 g, 72%) as a yellow solid: LCMS: 317 [M+1]+; 1H NMR (DMSO-d6) δ 1.36 (s, 9H), 3.10(q, 2H, J1 = 8.0 Hz, J2 = 16 Hz), 3.30 (q, 2H, J1 = 8.0 Hz, J2 = 16 Hz), 6.98 (d, 2H, J = 8 Hz), 7.38 (t, 1H, J = 7.2 Hz), 8.04 (d, 1H, J = 8.0 Hz).

Step 59d: tert-Butyl 2-(3-amino-2-chloropyridin-4-ylamino)ethylcarbamate (Compound 0603-84)

[0291] A mixture of compound 0602-84 (70 g, 0.221 mol), iron powder (62 g, 1.105 mol) and FeSO4 7H2O (18.5 g, 66 mmol) in a saturated aqueous NH4Cl solution (750 mL ) and MeOH (1400 mL) was heated at 80°C for 3 hours. The reaction was then filtered and washed with MeOH. The filtrate was concentrated and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with water and concentrated to give the title compound 0603-84 (55 g, 87%) as a red solid. LCMS: 287 [M+1]+; 1H NMR (DMSO-d6) δ 1.37 (s, 9H), 3.13(m, 4H), 4.69 (s, 2H), 5.76 (d, 1H, J = 5.2 Hz), 6.45 (d, 1H, J = 5.6 Hz), 6.92 (d, 1H, J = 5.2 Hz), 7.41 (d, 1H, J = 5.2 Hz).

Step 59e : tert-Butyl 2-(4-chloro-2-thioxo-2,3-dihydroimidazo[4,5-c]pyridin-1-yl)ethylcarbamate (Compound 604-84)

[0292] A mixture of compound 0603-84 (55 g, 0.192 mol), KOH (54 g, 0.959 mol), CS2 (73 g, 0.959 mol) in EtOH (500 mL) and H2O (50 mL) was stirred for 12 hours at 85°C. Then the mixture was cooled to room temperature and diluted with water. The mixture was adjusted to pH 7 with AcOH, filtered to give the title compound 604-84 (54.5 g, 87%) as a yellow solid: LCMS: 329 [M+1]+; 1H NMR (DMSO-d6) δ 1.20 (s, 9H), 3.33(s, 2H), 4.24 (t, 2H, J = 4.8 Hz), 6.89 (t, 1H, J = 5.2 Hz), 7.33 (d, 1H, J = 5.2 Hz), 8.14 (d, 1H, J = 5.2 Hz), 13.59 (s, 1H).

Step 59f: 1-(2-Aminoethyl)-4-chloro-1H-imidazo[4,5-c]pyridine-2(3H)-salthione (Compound 0605-84)

[0293] A mixture of compound 0604-84 (63.8 g, 0.194 mol) and TFA (150 ml, 1.94 mol) in dichloromethane (750 ml) was stirred for 2 hours at 25°C. The solvent was removed and dried to give the title compound 0605-84 (163 g) as a yellow solid which was used directly in the next step without further purification: LCMS: 229 [M+1]+; 1H NMR (DMSO-d6) δ 3.27(q, 2H, J1 = 5.2 Hz, J2 = 11.2 Hz), 4.47 (t, 2H, J = 6.0 Hz), 7.55 (d, 1H, J = 5.2 Hz), 7.92 (s, 2H), 8.20 (d, 1H, J = 5.2 Hz), 12.22 (s, 2H), 13.78 (s, 1H).

Step 59g: 4-Chloro-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione (Compound 0606-84)

[0294] A suspension of compound 0605-84 (163 g, 0.194 mol) in MeOH (1300 mL) was adjusted to pH 8 with Net3 (~100 mL) in an ice bath. Then pivalaldehyde (33.4 g, 0.388 mol) was added to the mixture and the mixture was stirred for 30 minutes at room temperature. NaBH3CN (48.76 g, 0.776 mol) was added to the mixture and the mixture was stirred at room temperature overnight. The resulting solid was filtered to give the title compound 0606-84 (38.6 g, two-step total yield: 67%) as a yellow solid: LCMS: 299 [M+1]+; 1H NMR (DMSO-d6) δ 0.79 (s, H), 2.36 (s, 2H) 2.95 (t, 2H, J = 6.0 Hz), 4.32 (t, 2H, J = 6.0 Hz), 7.49 (d, 1H , J = 5.6 Hz), 8.07 (d, 1H, J = 5.6 Hz).

Step 59h: 4-Amino-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione (Compound 0607-84)

[0295] A mixture of compound 0606-84 (11.4 g, 38.2 mmol) and sodium amide (30 g, 769 mmol) in 400 mL of liquid ammonia was stirred at 25°C for 24 hours in an autoclave. The ammonia was volatilized before opening the autoclave. Water was added carefully until all solids dissolved. This solution was adjusted to pH 7 with acetic acid and filtered to obtain the title compound 0607-84 (9 g, 84%) as a gray solid: LCMS: 280 [M+1]+; 1H NMR (DMSO-d6) δ 0.792 (s, 9H), 2.27 (s, 2H), 2.84 (m, 2H), 4.19 (m, 2H), 6.06 (s, 2H), 6.77 (m, 1H), 7.71 (m, 1H).

Step 59i: 5-Iodo-6-vinylbenzo[d][1,3]dioxol (Compound 010784)

[0296] To a solution of 3,4-(methylenedioxy)benzyl alcohol (1.8g, 12mmol) and CF3COOAg (3.434g, 15.5mmol) in dry CHCl3 (55ml) at -5°C was added I2 (3.9 g, 15.5 mmol) in portion. The resulting yellow mixture was kept at -5°C for 5 minutes, then filtered. The filtrate was washed with 20% Na2S2O3, dried and evaporated. The crude product was purified by silica gel column chromatography (petroleum ether) to obtain (6-iodobenzo[d][1,3]dioxol-5-yl)methanol (1.8 g, 56%) as a white solid. LCMS: 279[M+1]+; 1H NMR (DMSO-d6) δ 4.31 (d, 2H, J = 4.2 Hz), 5.40(t, 1H, J = 4.2 Hz), 6.03 (s, 2H), 7.03 (s, 1H), 7.34 (s, 2H).

[0297] (6-Iodobenzo[d][1,3]dioxol-5-yl)methanol (2.7 g, 9.7 mmol) in dry CH 2 Cl 2 was added dropwise in PCC (3.1 g, 14.6 mmol) in dry CH2Cl2 at 0°C under N2 atmosphere. The mixture was stirred at room temperature for 20 hours. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether) to obtain 6-iodobenzo[d][1,3]dioxol-5-carbaldehyde (2 g, 77%) as a white solid. . LCMS: 277[M+1]+; 1H NMR (DMSO-d6) δ 6.20 (s, 2H), 7.28 (s, 1H), 7.61 (s, 1H), 9.79 (s, 1H).

[0298] To a mixture of PPh3CH3I (5.5g, 13.5mmol) in dry THF was added t-BuOK (1.7g, 14.8mmol) at 0°C. The reaction mixture was stirred for 20 minutes. The above-prepared compound 6-iodobenzo[d][1,3]dioxol-5-carbaldehyde in THF was then added to the reaction mixture dropwise. After reaction, the crude product was purified by silica gel column chromatography (petroleum ether) to obtain the title compound 0107-84 (2.65 g, 78%) as a white solid. LCMS: 275 [M+1]+; 1H NMR (DMSO-d6) δ 5.24(d, 1H, J = 10.8Hz), 5.65 (d, 1H, J = 17.1 Hz), 6.07 (s, 2H), 6.73 (m, 1H), 7.28 (s, 1H), 7.39 (s, 1H).

Step 5 9j: 1-(2-(Neopentylamino)ethyl)-2-(6-vinylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4- amine (Compound 84)

[0299] A mixture of 0607-84 (100 mg, 0.36 mmol), 0107-84 (118 mg, 0.43 mmol), neocuproine hydrate (7.5 mg, 0.036 mmol), CuI (6.8 mg, 0.036 mmol) and NaOt-Bu (52 mg, 0.54 mmol) in anhydrous DMF (5 mL) was stirred for 12 hours at 110°C (oil bath) under nitrogen atmosphere. The solvent was poured into water, the mixture was then extracted with ethyl acetate. The solvents were removed and the crude product was purified by prep-TLC (20/1 CH 2 Cl 2 /MeOH) to obtain the title compound 84 (32 mg, 21%) as a yellow solid: m.p. 175~178 oC. LCMS: 547[M+1]+; 1H NMR (DMSO-d6) δ 0.77(s, 9H), 2.18(s, 2H), 2.72(t, 2H, J = 4.5 Hz), 4.21(t, 2H, J = 4.8 Hz), 5.31(d, 1H, J = 8.4 Hz), 5.77(d, 1H, J =13.5 Hz), 6.05(s, 2H), 6.28 (s, 2H), 6.81 (m, 2H), 7.22 (m, 1H), 7.32 ( s, 1H), 7.67 (d, 1H, J = 4.5 Hz).

Example 60: Preparation of 6-(4-amino-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)benzo[d][1,3]dioxol- 5-carbonitrile (Compound 89) Step 60a: 6-Iodobenzo[d][1,3]dioxol-5-carbonitrile (Compound 0107-89)

[0300] A mixture of 5,6-diiodobenzo[1,3]dioxol (1 g, 2.7 mmol) and CuCN (240 mg, 2.7 mmol) in DMF (15 mL) was stirred at 140°C for 16 hours. The mixture was filtered and the filtrate was added to water. The resulting brown solid was filtered and purified by silica geol column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the title compound 107-89 (450 mg, 61%) as a white solid: LCMS: 274[M+1]+; 1H NMR (DMSO-d6) δ 6.20 (s, 2H), 7.48 (s, 1H), 7.60 (s, 1H).

Step 60b: 6-(4-Amino-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)benzo[d][1,3]dioxol-5- carbonitrile (Compound 89)

[0301] Title compound 89 was prepared (26 mg, 11.4%) as a yellow solid from compound 0607-84 (150 mg, 0.54 mmol), 0107-89 (176 mg, 0.64 mmol), neocuproin hydrate (11.2 mg, 0.054 mmol), CuI (10.2 mg, 0.054 mmol) and NaOT-Bu (77 mg, 0.81 mmol) in anhydrous DMF (5 mL) using a similar procedure to that described for compound 84 (Example 59): m.p. 126~130 oC. LCMS: 425 [M+1]+; 1H NMR (DMSO-d6) δ 0.76(s, 9H), 2.20(s, 2H), 2.79(t, 2H, J = 4.8 Hz), 4.27(t, 2H, J = 4.5 Hz), 6.18(s, 2H), 6.31 (s, 2H), 6.83 (d, 1H, J = 4.5 Hz), 6.99 (s, 1H), 7.53 (s, 1H), 7.68 (s, 1H).

Example 61: Preparation of 2-(6-iodo-2,2-dimethylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-neopentylamino)ethyl)-1H-imidazo[4,5- c]pyridin-4-amine (Compound 01) Step 61a: 5,6-Diiodo-2,2-dimethylbenzo[d][1,3]dioxol (Compound 0107-101)

[0302] A mixture of catechol (10g, 91mmol), 2,2-dimethoxypropane (8.6g, 82.6mmol) and p-TsOH (33mg, 0.17mmol) in toluene (100ml) was stirred at reflux for 6 hours. After the reaction, the mixture was cooled to room temperature and NaHCO3 was added to neutralize the mixture. The solvent was removed and the residue was purified by distillation under reduced pressure at 36°C to obtain 2,2-dimethylbenzo[d][1,3]dioxol (2.34 g, 17%) as a yellow oil. 1H NMR (CDCl3-d6) δ 1.69 (s, 6H), 6.78(m, 4H).

[0303] A solution of 2,2-dimethylbenzo[d][1,3]dioxol compound 92.34 g, 15.6 mmol) in MeCN (80 ml) was added NIS (10.5 g, 46.8 mmol) and followed with TFA (3.56 g, 31.2 mmol). The solution was stirred overnight at room temperature. The solution was concentrated and the residue was purified by silica column chromatography (petroleum ether) to provide the title compound 0107-101 (5.6 g, 89%) as a white solid. 1H NMR (CDCl3-d6) δ 1.58 (s, 6H), 7.15(s, 2H).

Step 61b: 2-(6-Iodo-2,2-dimethylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c ] pyridin-4-amine (Compound 101)

[0304] Title compound 101 was prepared (31mg, 10%) as a white solid from compound 0607-84 (200mg, 0.72mmol), 0107-101 (431mg, 1.07mmol) , neocuproin hydrate (15 mg, 0.072 mmol), CuI 914 mg, 0.072 mmol) and NaOt-Bu (69 mg, 0.72 mmol) in anhydrous DMF (5 mL) using a procedure similar to that described for compound 84 ( Example 59): m.p.: 214-216°C; LCMS: 554 [M+1]+; 1H NMR (DMSO-d6) δ 0.76 (s, 9H), 1.60 (s, 6H), 2.16 (s, 2H), 2.73 (t, 2H, J = 5.6 Hz), 4.24(t, 2H, J = 5.6 Hz), 6.36 (s, 2H), 6.51 (s, 1H), 6.84 (d, 2H, J = 5.2 Hz), 7.38 (s, 1H), 7.70 (d, 1H, J = 5.2 Hz).

Example 62: Preparation of 1-(2-(Neopentylamino)ethyl)-2-(6-nitrobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 113) Step 62a: 5-Iodo-6-nitrobenzo[d][1,3]dioxol (Compound 0107113)

[0305] 1,3-benzodioxyl (10.0 g, 82 mmol) was added dropwise to the solution of concentrated HNO3 (65%~68%, 18 g) in H 2 O (39 g) at 60~65°C. The mixture was then heated to 90°C and stirred for 2 hours at this temperature. The mixture was cooled to room temperature and poured into ice/water, filtered to give 5-nitrobenzo[d][1,3]dioxol compound (12.0 g, 87%) as a yellow solid. LCMS: 168 [M+1]+; 1H NMR (DMSO-d6) δ 6.27 (s, 2H), 7.12 (d, 1H, J = 12 Hz), 7.76 (d, 1H, 3.2 Hz), 7.91 (dd, 1H, J1 = 12 Hz, J2 = 3.2 Hz).

[0306] The compound 5-nitrobenzo[d][1,3]dioxol (5.0 g, 30 mmol) was added in a portion of the solution of vaporized HNO3 and concentrated HNO3 (V/V=1/1, 120 mL ) at -10°C to -5°C. The mixture was stirred for 3 hours at this temperature and poured into ice/water, filtered to give the compound 5,6-dinitrobenzo[d][1,3]dioxol (7.0 g, quantitative) as a yellow solid. The compound was used directly without purification. 1H NMR (DMSO-d6) δ 6.39 (s, 2H), 7.86 (s, 2H).

[0307] The compound 5,6-dinitrobenzo[d][1,3]dioxol (6.0 g, 28.3 mmol) was added to the stirred glacial acetic acid 9120 mL) under N 2 atmosphere. After the mixture was heated to boiling, the heat source was removed and iron powder (4.75 g) added with vigorous stirring. Rapid spontaneous boiling occurred, the mixture turned dark and the exothermic reaction slowed down (2~5 minutes). The mixture was refluxed for 10 minutes and poured into ice/water. The orange-red product was isolated by filtration, dissolved in glacial acetic acid, and the solution filtered while heated. The filtrate was poured into ice-cold water. The orange-red solid product was isolated by filtration and dried to provide 6-nitrobenzo[d][1,3]dioxol-5-amine compound (4.35 g, 84%). LCMS: 183 [M+1]+; 1H NMR (DMSO-d6) δ 6.06 (s, 2H), 6.51 (s, 1H), 7.36 (s, 1H), 7.73 (s, 2H).

[0308] A suspension of 6-nitrobenzo[d][1,3]dioxol-5-amine 92.65 g, 14.6 mmol) in concentrated HCl 915 mL) and water (5 mL) was heated in a stream for 5 minutes and then cooled to 5°C with stirring. A solution of sodium nitrite (1.0 g, 14.4 mmol) in water (15 mL) was added until all solids dissolved. The solution was stirred for an additional 5 minutes and a solution of potassium iodide (2.4 g, 14.5 mmol) in water was then added rapidly with vigorous stirring at 5°C. The mixture was filtered and the residue was dissolved in dichloromethane, dried and purified by column chromatography (ethyl acetate/petroleum ether = 1/10) to provide the title compound 0107-113 (1.6 g, 38%) as a yellow solid. 1H NMR (DMSO-d6) δ 6.24 (s, 2H), 7.64 (s, 1H), 7.67 (s, 1H).

Step 62b: 1-(2-(Neopentylamino)ethyl)-2-(6-nitrobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 113)

[0309] Title compound 113 was prepared 940mg, 26%) as a yellow solid from compound 0607-84 (100mg, 0.358mmol), 0107-113 (137mg, 0.466mmol), necocuproine (8mg , 0.036 mmol), CuI (7 mg, 0.036 mmol), and non-t-Bu (52 mg, 0.537 mmol) in anhydrous DMF (5 mL) using a procedure similar to that described for compound 84 (Example 59): m.p. 111~114 oC. LCMS: 445[M+1]+, 1H NMR (DMSO-d6) δ 0.72 (s, (H), 1.61 (s, 1H), 2.12 (s, 2H), 2.74 (t, 2H, J =5.2 Hz ), 4.21(t, 2H, J = 5.2 Hz), 6.16 (s, 1H), 6.18 (s, 2H), 6.49 9s, 2H), 6.85 (d, 1H, J = 6.4 Hz), 7.73 (d, 1H, J = 6.4 hz), 7.85 (s, 1H).

Example 63: Preparation of 2-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c] pyridin-4-amine (Compound 111) Step 63a: 6-Iodo-N,N-dimethylbenzo[d][1,3]dioxol-5-amine (Compound 0107-111)

[0310] To the solution of 3,4-(methylenedioxy)aniline (8g, 58.3mmol) in AcOH (120ml) was added Ac2O (48ml). The mixture was stirred overnight. After the reaction, the mixture was poured into the saturated NaHCO3 solution, and then filtered. The filtrate was extracted with ethyl acetate to give N-(benzo[d][1,3]dioxol-5-yl)acetamide (10g, 95%). LCMS: 180[M+1]+.; 1H NMR (DMSO-d6) δ 2.0 (s, 3H), 5.96 (s, 2H), 6.82 (d, 1H, J = 8.1 Hz), 6.91 (d, 1H, J = 2.1 Hz), 7.30 (d, 1H, J = 1.8 Hz), 9.84 (s, 1H).

[0311] A 1.0 M solution of iodine monochloride in methylene chloride (72.6 mL) was added dropwise to the N-(benzo[d][1,3]dioxol-5-yl)acetamide solution. (10 g, 55.8 mmol) in methylene chloride (66 mL) in acetic acid 911 mL). The mixture was stirred under nitrogen overnight and then washed with saturated sodium thiosulfate (2 x 150 mL) and brine (150 mL). The methylene chloride solution was dried (MgSO4) and evaporated, and the residue was purified by silica gel column chromatography (CH2Cl2/petroleum 20/1) to obtain N-(6-iodobenzo[d][1.3 ]dioxol-5-yl)acetamide (3.7 g, 22%) as a white solid. LCMS: 306 [M+1]+; 1H NMR (DMSO-d6) δ 2.00 (s, 3H), 6.06 (s, 2H), 6.95 (s, 1H), 7.37 (s, 1H), 9.34 (s, 1H).

[0312] A solution of N-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (200 mg, 0.656 mmol) and NaOH (1.31 g, 32.8 mmol) in ethanol ( 26 ml) and water (6 ml) was heated to reflux with stirring for 4 hours. The mixture was cooled and the solvents removed under vacuum. The residue was partitioned between methylene chloride (100ml) and water (100ml). The organic layer was washed with water (2 x 100 mL), dried (mgSO4) and evaporated in vacuo to give 6-iodobenzo[d][1,3]dioxol-5-amine (170 mg, 98%) as a orange solid. LCMS: 264 [M+1]+; 1H NMR (DMSO-d6) δ 4.88 (s, 2H), 5.87 (s, 2H), 6.47 (s, 1H), 7.07 (s, 1H).

[0313] To a solution of 6-iodobenzo[d][1,3]dioxol-5-amine (1 g, 3.8 mmol) and paraformaldehyde (1.14 g, 38 mmol) in methanol 910 mL) was added NaBH3CN (2.39 g, 38 mmol) slowly with stirring. The mixture was heated at 50°C for 4 hours. Water (100 ml) was added and extracted with methylene chloride (100 ml). The organic chamber was washed with brine (100 mL), dried (MgSO4) and evaporated in vacuo to give the crude product of the title compound 0107-111 (1.16 g) as a brown oil which was used directly for the next step. without further purification. LCMS: 292 [M+1]+; 1H NMR (DMSO-d6) δ 2.56 (s, 6H), 6.02 (s, 2H), 6.96 (s, 1H), 7.32 (s, 1H).

Step 63b: 2-(6-(Dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin- 4-amine (Compound 111)

[0314] Title compound 111 was prepared (20mg, 6.6%) as a brown solid from compound 0607-84 (190mg, 0.68mmol), 0107-111 9200mg, 0.68mmol ), neocuproin hydrate (14 mg, 0.068 mmol), CuI (12 mg, 0.068 mmol) and NaOt-Bu (66 mg, 0.068 mmol) in anhydrous DMF (6 mL) using a procedure similar to that described for compound 84 ( Example 59): LCMS: 443 [M+1]+; 1H NMR (DMSO-d6) δ 0.748 (s, 9H), 2.16 (s, 2H), 2.63 (s, 6H), 2.74 (t, 2H, J = 6.0 Hz), 4.21 (t, 2H, J = 6.0 Hz) 5.94 (s, 2H), 6.16 (s, 1H), 6.38 (s, 2H), 6.84 (d, 1H, J = 6.0 Hz), 7.01 (s, 1H), 7.70 (d, 1H, J = 5.6 Hz).

Example 64: Preparation of 2-(6-((dimethylamino)methyl)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4.5 -c]pyridin-4-amine (Compound 115) Step 64a: Compound N-((6-Iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide (Compound 0107-115)

[0315] To a solution of 3,4-methylenedioxybenzylamine (10 g, 66.2 mmol) in acetic acid (50 mL) was added acetic anhydride (15.27 g, 150 mmol). The mixture was stirred at 20°C for 30 minutes. Then it was adjusted to pH 7 with 10% NaOH. The mixture was filtered to obtain a solid which was washed with water and dried in vacuo to give the N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide as a white solid (9.24 g, 77%) . LC-MS: 194 [M+1]+; 1H-NMR (DMSO-d6): δ 1.84 (s, 3H), 4.12 (d, 2H, J = 6.4 Hz), 5.98 (s, 2H), 6.71 (m, 2H), 6.83 (m, 2H), 8.28 (s, 1H).

[0316] N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide (9.24 g, 47.9 mmol) was added to a 1.0 M solution of iodine monochloride in methylene chloride (80 mL). The mixture was stirred at room temperature for 2 hours, then the mixture was poured into 10% Na2S2O3 and stirred until the red color faded. It was then extracted with CH2Cl2 and the organic layer was washed with water and brine, dried and concentrated to give the crude product which was purified by column chromatography (mobile phase: petroleum/methylene chloride = 1/19) to give the compound N-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide as a white solid (5.82 g, 38%). LC-MS: 320 [M+1]+. 1H-NMR (DMSO-d6): δ 1.89 (s, 3H), 4.11 (d, 2H, J = 6.0 Hz), 6.04 (s, 2H), 7.07 (s, 1H), 7.37 (s, 1H), 8.28 (t, 1H, J = 6.0 Hz).

[0317] N-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide 92.4 g, 7.5 mmol) was added to a solution of methanolic hydrochloric acid (4N) (60 ml). The mixture was stirred at 80°C overnight. The solvent was removed and the residue dissolved in water, adjusted to pH 7 with 10% NaHCO 3 , filtered to obtain (6-iodobenzo[d][1,3]dioxol-5-yl)methaneamide as a yellow solid (1.76 g, 85%). LC-MS: 278 [M+1]+. 1H-NMR (DMSO-d6): δ 1.88 (s, 2H), 3.57 (s, 2H), 6.02 (s, 2H), 7.13 (s, 1H), 7.33 (s, 1H).

[0318] A mixture of (6-iodobenzo[d][1,3]dioxol-5-yl)methaneamide (1.76 g, 6.35 mmol), NaBH3CN (4.00 g, 63.5 mmol), and formaldehyde 91.9 g, 63.5 mmol) in methanol (10 mL) was stirred at 50°C for 2 hours. The solvent was removed and the residue was dissolved in CH2Cl2, washed with water and brine, dried and concentrated to give the title compound 0107-115 as a yellow solid (700mg, 36%). LC-MS: 306 [M+1]+. 1H-NMR (DMSO-d6): δ 2.15 (s, 6H), 3.29 (s, 2H), 6.02 (s, 2H), 6.95 (s, 1H), 7.33 (s, 1H).

Step 64b: 2-(6-((Dimethylamino)methyl)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c ]pyridin-4-amine (Compound 115)

[0319] Title compound 115 was prepared 927 mg, 15%) as a yellow solid from compound 0607-84 9100 mg, 0.358 mmol), 0107-115 (120 mg, 0.394 mmol), CuI (7 mg, 0.0358 mmol), t-BuONa (34 mg, 0.0358 mmol), neoucuproin (8 mg, 0.0358 mmol), and DMF (3 mL) using a procedure similar to that described for compound 84 (Example 59) : m.p. 81~86 oC. LC-MS: 457.2 [M+1]+. 1H-NMR (DMSO-d6): δ 0.77 (s, 9H), 2.16 (s, 8H), 2.70 (m, 2H), 3.48 (s, 2H), 4.18 (m, 2H), 6.00 (s, 2H ), 6.28 (m, 2H), 6.64 (s, 1H), 6.80 (m, 1H), 6.97 (s, 1H), 7.68 (m, 1H).

Example 65: Preparation of 2-(6-Ethylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4 -amine (Compound 85) Step 65a: 5-Ethyl-6-iodobenzo[d][1,3]dioxol (Compound 0107-85)

[0320] t-BuOK (7.77 g, 69.3 mmol) was added portionwise to a suspension of the methyltriphenylphosphonium iodide compound (28.0 g, 68.3 mmol) in dry THF (250 mL) for 10 minutes at 0°C . The resulting yellow suspension was stirred for 20 minutes at this temperature. A solution of piperonal (8.0 g, 53.3 mmol) in was added dropwise to the above suspension and the mixture was stirred for 1 hour at 0°C. The reaction mixture was concentrated and the residue was purified by column chromatography (petroleum ether) to provide the compound 5-vinylbenzo[d][1,3]dioxol (7.4 g, 94%) as a colored liquid. 1H-NMR (DMSO-d6): δ 5.09 (d, 1H, J = 11.2 Hz), 5.68 (d, 1H, J = 18 Hz), 6.00 (s, 2H), 6.63 (1, 1H, J1 = 11.2 Hz, J2 = 18 Hz), 6.85 (m, 2H), 7.11 (s, 1H).

[0321] A mixture of 5-vinylbenzo[d][1,3]dioxol (6.0 g, 40.5 mmol) and 10% Pd/C (840 mg) in MeOH (50 mL) was hydrogenated for 8 hours at 10 atm. Then Pd/C was filtered and the MeOH was removed to give the compound 5-ethylbenzo[d][1,3]dioxol (3.0 g, 50%) as a colored liquid. 1H-NMR (DMSO-d6): δ 1.11 (t, 3H, J = 7.2 Hz), 2.50 (q, 2H, J1 = 7.2 Hz, J2 = 16 Hz), 5.93 (s, 2H), 6.64 (d, 1H, J = 8 Hz), 6.77 (m, 2H).

[0322] A mixture of the compound 5-ethylbenzo[d][1,3]dioxol (3.0g, 20mmol), NIS (6.0g, 22mmol) and TFA (2.3g, 20mmol) in 30 ml of CH3CN was stirred for 5 hours at room temperature. The saturated Na2S2O3 solution was then added dropwise to the mixture until the color was faded. CH3CN was evaporated in vacuo and the mixture was extracted with ethyl acetate (20ml x 2). The organic phase was dried and concentrated to obtain the title compound 0107-85 (5.3g, 96%) as a yellow solid. GC-MS 276 [M+1]+, 1H NMR (DMSO-d6): δ 1.06 (t, 3H, J = 7.6 Hz), 2.57 (q, 2H, J = 7.6 Hz), 6.00 (s, 2H) , 6.93 (s, 1H), 7.30 (s, 1H).

Step 65b: 2-(6-Ethylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 85)

[0323] Title compound 85 was prepared (40 mg, 26%) as a yellow solid obtained from compound 0607-84 9100 mg, 0.358 mmol), 0107-85 (172 mg, 0.466 mmmol), neocuproine (8 mg, 0.0358 mmol), CuI (7 mg, 0.036 mmol), and t-BuONa (52 mg, 0.537 mmol) in anhydrous DMF (5 mL) using a procedure similar to that described for compound 84 (Example 59): m.p. 145~147 oC, LCMS: 428 [M+1]+ 1H NMR (DMSO-d6): δ 0.79 (s, 9H), 1.14 (t, 3H, J =7.2 Hz), 1.65 (bs, 1H), 2.18 (s, 2H), 2.75 (t, 2H, J = 5.6 Hz), 2.78 (q, 2H, J = 7.6 Hz), 4.23 (t, 2H, J = 6.0 Hz), 6.01 (s, 2H), 6.21 (s, 2H), 6.72 (s, 1H), 6.82 (d, 1H, J = 5.6 Hz), 6.96 (s, 1H), 7.69 (d, 1H, J = 5.2 Hz).

Biological Assay:

[0324] As previously noted, the derivatives defined in the present invention possess anti-proliferation activity. These properties can be evaluated, for example, using one or more of the procedures listed below:

(a) An in vitro assay that determines the ability of a test compound to inhibit Hsp90 chaperone activity

[0325] The Hsp90 chaperone assay was performed to mediate the ability of the HSP90 protein to refold the heat-denatured lucierase protein. HSP90 was first incubated with different concentrations of the test compounds in a denaturation buffer (25 mM Tris, pH 7.5, 8 mM MgSO4, 0.01% bovine gamma globulin and 10% glycerol) at room temperature for 30 minutes. . Luciferase protein was added to denature the mixture and incubated at 50°C for 8 minutes. The final concentration of HSP90 and luciferase in the denaturation mixture was 0.375 µM and 0.125 µM respectively. A 5 µL sample of the denaturation mixture was diluted into 25 µL of renaturation buffer (25 mM Tris, pH 7.5; 8 mM MgSO4, 0.01% bovine gamma globulin and 10% glycerol, 0.5 mM ATP, 2 mM DTT, 5 mM KCl, 0.3 µM HSP70 and 0.15 µM HSP40). The renaturation reaction was incubated at room temperature for 150 minutes, followed by diluting 10 µL of the renatured sample into 90 µL of the luciferin reagent (Luclite, PerkinElmer Life Science). The mixture was incubated in the dark for 5 minutes before reading the luminescence signal on a TopCount reader plate (PerkinElmer Life Science).

(b) Assay (Fluorescence Polarization) of competition for binding of HSP90

[0326] A GM-labeled fluorescein isothiocyanate (FITC) was purchased from InvivoGen (anti-fgl-1). The interaction between HSP90 and the labeled GM forms the basis for the fluorescence polarization assay. A GM-labeled fast-tipping FITC emits random light with respect to the plane of the plane of polarization into excited light, resulting in a lower degree of polarization value (mP). When GM is connected to the HSP90, the complex tipping decreases and the emitted light is polarized, resulting in a higher mP value. This binding competition assay was performed in a 96-well plate and with each of the assays containing 10 and 50 nM of the labeled Gm and the purified HSP90 protein (Construction Assay, SPP-776F) respectively. The assay of buffer containing 20 mM HEPES (pH 7.3), 50 mM KCl, 1 mM DTT, 50 mM MgCl2, 20 mM Na2MoO4, 0.01% NP40 with 0.1 mg/ml of bovine gamma globulin. Compounds are diluted in DMSO and added at the end of the assay before the GM labeled with a concentration range of 20 µM to 2 nM. The mP value was determined by BioTek Synergy II with background subtraction after 24 hours incubation at 4°C.

[0327] Table B below lists representative compounds of the invention and their activity in the HSP90 assay. In this assay, the following grid was used: I > 10 μ M; 10 μM > II > 1 μM; 1 μM > III > 0.1 μiM; and IV < 0.1 μM for IC50.

[0328] A representative compound of the invention was shown to have a favorable pharmacological kinetic (PK) profile and a high degree of penetration into the brain after systemic administration. In a tMAO model (Dellovade, T., “Annu. Rev. Neurosci.”, 2006, 29, 539-563), a single i.v. 10 mg/kg of the compound in the rat was shown to have a significant overall reduction in cerebral infarct volume by approximately 33% at 4 hours post-tMCAO.

[0329] The patent literature and scientific publications referred to herein establish the knowledge that is available to those skilled in the art. All US patents and published or unpublished US patent applications cited herein are incorporated by reference. All foreign patents and published patent applications cited herein are incorporated herein by reference. All other references, documents, manuscripts and published scientific literature cited herein are incorporated into this application by reference.

[0330] While this invention has been particularly shown and described with reference to preferred embodiments thereof, it should be understood by those skilled in the art that various changes in form and detail may be made in this invention without departing from the scope of the invention encompassed by the appended claims.

Claims (18)

1. Compound, which is characterized by the fact that it is represented by the formula (I):

or a pharmaceutically acceptable salt thereof, where: U is N or CH; W is hydrogen, halogen, amino, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2 , CN, N3 , sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; X is O, S, S(O), S(O)2 , N(R8 ), C(O), where R8 is hydrogen, acyl, aliphatic or substituted aliphatic; Y is independently hydrogen, halogen, NO 2 , CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; Q is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or heterocycloalkyl; V is hydrogen, linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, which one or more methylenes may be interrupted or terminated by O, S, S(O), SO2, N (R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl; substituted or unsubstituted cycloalkyl; where R8 is hydrogen, acyl, aliphatic or substituted aliphatic. 2. Compound, according to claim 1, which is characterized by the fact that it is represented by the formula (II):

or a pharmaceutically acceptable salt thereof, wherein X2 and X5 are independently CH or N; R21-R23 are independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy substituted, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , heterocyclyl, substituted heterocyclyl, cycloalkyl, or substituted cycloalkyl; R22 and R23 can be taken together from the carbon to which they are attached to form a 5-8 membered saturated or unsaturated fused cyclic ring, optionally substituted with 0-3 heteroatom; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, hydroxy, substituted hydroxy, amino, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; X is O, S, S(O), S(O) 2 , N(R 8 ) or C(O); Y is independently hydrogen, halogen, NO 2 , CN, or lower alkyl; and Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino. 3. Compound, according to claim 1, characterized in that it is represented by the formula (III):

or a pharmaceutically acceptable salt thereof, wherein X1-X5 are independently N or CR21, wherein R21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3 , substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, hydroxy, substituted hydroxy, amino, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; X is O, S, S(O), S(O) 2 , N(R 8 ) or C(O); Y is independently hydrogen, halogen, NO 2 , CN, or lower alkyl; and Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino. 4. Compound, according to claim 1, which is characterized by the fact that it is represented by the formula (IV):

or a pharmaceutically acceptable salt thereof, wherein X2 and X5 are independently CH or N; R21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic , substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Cy is a 5-8 membered saturated or unsaturated fused cyclic ring, optionally substituted with 0-3 heteroatom; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, Hydroxy, substituted hydroxy, amino, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; X is O, S, S(O), S(O) 2 , N(R 8 ) or C(O); Y is independently hydrogen, halogen, NO 2 , CN, or lower alkyl; and Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino. 5. Compound, according to claim 1, which is characterized by the fact that it is represented by the formula (V):

or pharmaceutically acceptable salt thereof, wherein X2 and X5 are independently CH or N; R21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic , substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Y1 and Y3 are independently O, S, N(R8), CH(R21); n is 1, 2, or 3; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C=O; M3 is absent, C=O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, hydroxy, substituted hydroxy, amino, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R10 and R20 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; X is O, S, S(O), S(O) 2 , N(R 8 ) or C(O); Y is independently hydrogen, halogen, NO 2 , CN, or lower alkyl; and Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino. 6. Compound, according to claim 1, which is characterized by the fact that it is of the formula:

or a pharmaceutically acceptable salt thereof. 7. Compound, according to claim 1, which is characterized by the fact that it is of the formula:

or a pharmaceutically acceptable salt thereof. 8. Compound according to claim 1, which is characterized in that it is selected from the compounds outlined below, or a pharmaceutically acceptable salt thereof:

9. A pharmaceutical composition, which is characterized in that it is for use in the treatment of a proliferative cell disorder that requires or is facilitated by the expression of an HSP90 protein and comprises as an active ingredient, a compound as defined in any one of of claims 1 to 8, and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 8 which is for use in the treatment of a cell proliferative disorder which requires or is facilitated by the expression of an HSP90 protein. 11. A compound for use according to claim 10, which is characterized in that said cell proliferative disorder is cancer. 12. A compound for use according to claim 11, which is characterized in that the cancer is selected from the group consisting of papilloma, blastoglioma, Kaposi's sarcoma, melanoma, non-small cell lung cancer, ovarian cancer, prostate cancer, colon cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, lung cancer, colorectal cancer, thyroid cancer, pancreatic cancer, cell carcinoma kidney, gastric cancer, hepatocellular carcinoma, neuroblastoma, leukemia, lymphoma, cancer of the vulva, Hodkins disease and Burkitt's cancer. 13. A compound according to any one of claims 1 to 8, which is characterized in that it is for use in the treatment of an autoimmune or neurodegenerative disease. 14. A compound according to claim 13, which is characterized in that the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, polyglutamine disease, seizure, striatonigral degeneration, supranuclear palsy progressive, torsion dystonia, dyskinesia and spasmodic torticollis, familial tremor, Gilles de la Tourette syndrome, diffuse Lewy body disease, progressive supranuclear palsy, Pick's disease, intracerebral hemorrhage, primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis , hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia and Shy-Drager syndrome. 15. Compound, for use according to claim 10 or claim 13, which is characterized in that said compound has the formula:

or a pharmaceutically acceptable salt thereof. 16. A compound for use according to claim 10, which is characterized in that said proliferative cell disorder is a cancer selected from non-small cell lung cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, renal cell carcinoma, gastric cancer, hepatocellular carcinoma. 17. Compound according to claim 16, which is characterized in that said cancer is selected from non-small cell lung cancer and lung cancer. 18. Compound according to any one of claims 1 to 8, which is characterized in that it is for use in the treatment of inflammatory diseases and/or disorders of the immune system selected from Rheumatoid Arthritis (RA), Osteoarthritis , Juvenile chronic arthritis, Graft VERSUS host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's disease, Inflammatory bowel diseases, Ulcerative colitis, Alcoholic hepatitis, Diabetes, Sjoegren's syndrome, Multiple sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain, and Lupus systemic erythematosus.